bluuebunny/crossref_metadata_2025 huggingface dataset:
Being a Good Mom
Authors: Elliott Sinikka , Powell Rachel , Brenton Joslyn
Published: May 2013

The tenacity of the intensive mothering ideology—the notion that good mothers should invest vast amounts of time, money, energy, and emotional labor in mothering—is well documented, particularly among affluent White mothers. Drawing on 16 interviews with low-income, Black single mothers, we analyze how gender, race, class, and the ideology of intensive mothering intersect to shape these mothers’ parenting. Mothers repeatedly emphasized the importance of sacrifice, self-reliance, and protection. In short, good mothers sacrifice for their children; they are self-reliant and teach their children to be this way too; and they protect their children. We argue that low-income mothers embrace and perform intensive mothering in the absence of larger social supports for their children’s upbringing and at a cost to their own emotional and physical well-being.
Earthly Powers and Affective Environments: An Ontological Politics of Flood Risk
Authors: Whatmore Sarah J
Published: May 2013

In this article I set out to trace some of the implications of recharging the political potency of nature in more-than-human terms. This shifts attention from a biopolitical focus on the inventiveness of the life sciences and what this means in terms of the emergence of ‘cyborg’ political subjects to an onto-political focus on the inventiveness of knowledge controversies and what these mean for techno-political practices. Specifically, the article examines the onto-politics of ‘natural’ hazard events and their capacity to force thought in those affected by them, and so to place new demands on research practices in terms of rendering such events affective and amenable to political interrogation. I work these arguments through the demanding experimental ethos of the philosopher Isabelle Stengers, for whom scientific practices produce reliable knowledge claims only in so far as the questions they address are at risk of being redefined by the phenomena mobilized in them, and who extends this ethos to elaborate an understanding of, even a test for, an adequate political theory and practice. I do so with reference to a recent research experiment in which I collaborated with social and natural scientists and people affected by flooding in the UK.
Protecting boundaries of consent in clinical research
Authors: Bristol Shirley T , Hicks Rodney W
Published: May 2013

Successful clinical research outcomes are essential for improving patient care. Achieving this goal, however, implies an effective informed consent process for potential research participants. This article traces the development of ethical and legal requirements of informed consent and examines the effectiveness of past and current practice. The authors propose the use of innovative monitoring methodologies to improve outcomes while safeguarding consent relationships and activities. Additional rigorous research will help direct policy efforts at standardizing quality improvement processes.
Enhancing Crime Control Partnerships Across Government
Authors: Brewer Russell
Published: May 2013

This article discusses the importance of trust in furthering crime control partnerships among government agencies. Drawing upon fieldwork undertaken on American and Australian waterfronts, evidence is presented showing that trust played an integral role in shaping interagency partnerships at both sites. In abundance, trust was shown to help build social capital and promote harmonious relationships, whereas when lacking, collaborative activity was stunted. This article examines the successes and failures of partnerships in each case study, and concludes by identifying a range of factors that have been shown to promote trust, build social capital, and enable interagency partnerships to flourish.
Visual analysis of contagion in networks
Authors: von Landesberger Tatiana , Diel Simon , Bremm Sebastian , Fellner Dieter W
Published: May 2013

Contagion is a process whereby the collapse of a node in a network leads to the collapse of neighboring nodes and thereby sets off a chain reaction in the network. It thus creates a special type of time-dependent network. Such processes are studied in various applications, for example, in financial network analysis, infection diffusion prediction, supply-chain management, or gene regulation. Visual analytics methods can help analysts examine contagion effects. For this purpose, network visualizations need to be complemented with specific features to illustrate the contagion process. Moreover, new visual analysis techniques for comparison of contagion need to be developed.

In this paper, we propose a system geared to the visual analysis of contagion. It includes the simulation of contagion effects as well as their visual exploration. We present new tools able to compare the evolution of the different contagion processes. In this way, propagation of disturbances can be effectively analyzed. We focus on financial networks; however, our system can be applied to other use cases as well.
Multi-aspect visual analytics on large-scale high-dimensional cyber security data
Authors: Chen Victor Y , Razip Ahmad M , Ko Sungahn , Qian Cheryl Z , Ebert David S
Published: May 2013

In this article, we present a visual analytics system, SemanticPrism, which aims to analyze large-scale high-dimensional cyber security datasets containing logs of a million computers. SemanticPrism visualizes the data from three different perspectives: spatiotemporal distribution, overall temporal trends, and pixel-based IP (Internet Protocol) address blocks. With each perspective, we use semantic zooming to present more detailed information. The interlinked visualizations and multiple levels of detail allow us to detect unexpected changes taking place in different dimensions of the data and to identify potential anomalies in the network. After comparing our approach to other submissions, we outline potential paths for future improvement.
Young children’s cognitive achievement: Home learning environment, language and ethnic background
Authors: Frumkin Lara A
Published: May 2013

For decades, research has shown differences in cognitive assessment scores between White and minority ethnic group(s) learners as well as differences across different minority ethnic groups. More recent data have indicated that the home learning environment and languages spoken can impact cognitive assessment and other corollary outcomes. This study uses the Millennium Cohort Study to jointly assess how minority ethnic group, home learning environment and home languages predict child cognitive assessment scores. Regression analyses were conducted using two assessment measures. The following is hypothesised: (1) cognitive achievement scores vary by minority ethnic group, (2) more home learning environment in early childhood leads to higher cognitive development scores and (3) English only in the home yields the highest cognitive scores while no English in the home yields the lowest. Findings reveal that there are differences in cognitive scores along ethnic group categories although there are also some unexpected findings. Home learning environment does not play as large a role as was predicted in raising the assessment scores overall for learners while speaking English in the home does, irrespective of ethnic background.
Methodological Issues in National-Comparative Research on Cultural Tastes: The Case of Cultural Capital in the UK and Finland
Authors: Purhonen Semi , Wright David
Published: May 2013

Drawing on two projects which develop the methodological model of Bourdieu’s Distinction in the UK and Finland, this paper explores the issues raised by the use of multiple correspondence analysis (MCA) and mixed methods in comparative work on cultural tastes. By identifying the problems in the construction of two comparable yet nationally relevant research instruments, the paper considers the importance of the similarities and differences in the meaning of items in different national spaces for Bourdieu-inspired comparative analysis. The paper also reports on the evident similarities between the two constructed spaces and draws on the dialogue between quantitative and qualitative methods enabled by MCA in examining what different positions in social space appear to mean in these countries. It concludes by suggesting that, whilst Bourdieu’s model provides a robust set of methods for exploring relations between taste and class within nations, when used appropriately, it can also provide particular insight for the comparison of national fields.
The developing xylem transcriptome and genome-wide analysis of alternative splicing in Populus trichocarpa(black cottonwood) populations
Authors: Bao Hua , Li Eryang , Mansfield Shawn D , Cronk Quentin CB , El-Kassaby Yousry A , Douglas Carl J
Published: May 2013

Background

Alternative splicing (AS) of genes is an efficient means of generating variation in protein structure and function. AS variation has been observed between tissues, cell types, and different treatments in non-woody plants such as Arabidopsis thaliana (Arabidopsis) and rice. However, little is known about AS patterns in wood-forming tissues and how much AS variation exists within plant populations.

Results

Here we used high-throughput RNA sequencing to analyze the Populus trichocarpa (P. trichocarpa) xylem transcriptome in 20 individuals from different populations across much of its range in western North America. Deep transcriptome sequencing and mapping of reads to the P. trichocarpa reference genome identified a suite of xylem-expressed genes common to all accessions. Our analysis suggests that at least 36% of the xylem-expressed genes in P. trichocarpa are alternatively spliced. Extensive AS was observed in cell-wall biosynthesis related genes such as glycosyl transferases and C2H2 transcription factors. 27902 AS events were documented and most of these events were not conserved across individuals. Differences in isoform-specific read densities indicated that 7% and 13% of AS events showed significant differences between individuals within geographically separated southern and northern populations, a level that is in general agreement with AS variation in human populations.

Conclusions

This genome-wide analysis of alternative splicing reveals high levels of AS in P. trichocarpa and extensive inter-individual AS variation. We provide the most comprehensive analysis of AS in P. trichocarpa to date, which will serve as a valuable resource for the plant community to study transcriptome complexity and AS regulation during wood formation.
Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4–ALK-rearranged non–small–cell lung cancer harbored coexisting EGFRmutation
Authors: Miyanaga Akihiko , Shimizu Kumi , Noro Rintaro , Seike Masahiro , Kitamura Kazuhiro , Kosaihira Seiji , Minegishi Yuji , Shukuya Takehito , Yoshimura Akinobu , Kawamoto Masashi , Tsuchiya Shinichi , Hagiwara Koichi , Soda Manabu , Takeuchi Kengo , Yamamoto Nobuyuki , Mano Hiroyuki , Ishikawa Yuichi , Gemma Akihiko
Published: May 2013

Background

The EML4–ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non–small–cell lung cancers (NSCLCs). The EML4–ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.

Case presentation

We report that a case of EML4–ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.

Conclusions

We described the first clinical report of a patient with EML4–ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4–ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4–ALK-positive NSCLC.
Antidiabetic and antioxidant properties of Ficus deltoidea fruit extracts and fractions
Authors: Misbah Hasni , Aziz Azlina Abdul , Aminudin Norhaniza
Published: May 2013

Background

Diabetes is a serious metabolic disorder affecting the metabolism of carbohydrate, protein and fat. A number of studies have shown that diabetes mellitus is associated with oxidative stress, leading to an increased production of reactive oxygen species.Ficus deltoideais traditionally used in Malaysia for regulating blood sugar, blood pressure and cholesterol levels. The use ofF.deltoideaas an alternative medicinal herb is increasingly gaining popularity with the sale ofF.deltoideatea bags and capsules in the local market. The present study was undertaken to investigate the antidiabetic and antioxidant activities of the fruits from different varieties ofF.deltoidea, employingin vitromethods.

Method

Two fruit varieties ofF.deltoidea(var.angustifolia(SF) and var.kunstleri(BF)) were extracted separately using double-distilled water. The resulting aqueous extracts were partitioned using ethyl acetate to obtain the ethyl acetate and water fractions. The crude aqueous extracts and the corresponding fractions were evaluated for their phenolic, flavonoid, sugar and protein contents. Protein profiling of the extracts and fractions were also carried out by means of SDS-PAGE and SELDI-TOF MS. Antidiabetic activities were assessed based on the ability of the samples to inhibit yeast and mammalian α-glucosidase as well as α-amylase. Antioxidant capacities were examined by measuring the ability of the samples to reduce ferric ions and to scavenge DPPH, superoxide anion, ABTS and nitric oxide radicals.

Results

The crude extracts and fractions of SF and BF inhibited both yeast and rat intestinal α-glucosidases in a dose-dependent manner, but did not inhibit porcine pancreatic α-amylase. The water fraction of BF showed the highest percentage of α-glucosidase inhibition while having the highest amount of protein (73.33 ± 4.99 μg/mg fraction). All the extracts and fractions exhibited antioxidant activities, with SF crude extract showing the highest antioxidant activity and phenolic content (121.62 ± 4.86 mg/g extract). Fractionation of the crude extracts resulted in loss of antioxidant activities. There was no positive correlation between phenolic and flavonoid content with α-glucosidase inhibitory activities. However, phenolic content correlated well with antioxidant activities of the crude extracts but not with the fractions.

Conclusions

The antioxidant activities of the fruits ofF.deltoideamight be asserted by the phenolic content but other polar plant components were possibly involved in the antidiabetic properties. The study of these compounds having both antihyperglycemic and antioxidant activities may provide a new approach in the treatment of diabetes mellitus.
Folic acid-conjugated silica capped gold nanoclusters for targeted fluorescence/X-ray computed tomography imaging
Authors: Zhou Zhijun , Zhang Chunlei , Qian Qirong , Ma Jiebing , Huang Peng , zhang Xi , Pan Liyuan , Gao Guo , Fu Hualin , Fu Shen , Song Hua , Zhi Xiao , Ni Jian , Cui Daxiang
Published: May 2013

Background

Gastric cancer is 2th most common cancer in China, and is still the second most common cause of cancer-related death in the world. Successful development of safe and effective nanoprobes for in vivo gastric cancer targeting imaging is a big challenge. This study is aimed to develop folic acid (FA)-conjugated silica coated gold nanoclusters (AuNCs) for targeted dual-modal fluorescent and X-ray computed tomography imaging (CT) of in vivo gastric cancer cells.

Method

AuNCs were prepared, silica was coated on the surface of AuNCs, then folic acid was covalently anchored on the surface of AuNCs, resultant FA-conjugated AuNCs@SiO2 nanoprobes were investigated their cytotoxicity by MTT method, and their targeted ability to FR(+) MGC803 cells and FR(−) GES-1 cells. Nude mice model loaded with MGC803 cells were prepared, prepared nanoprobes were injected into nude mice via tail vein, and then were imaged by fluorescent and X-ray computed tomography (CT) imaging.

Results

FA-conjugated AuNCs@SiO2 nanoprobes exhibited good biocompatibility, and could target actively the FR(+) MGC-803 cells and in vivo gastric cancer tissues with 5 mm in diameter in nude mice models, exhibited excellent red emitting fluorescence imaging and CT imaging.

Conclusion

The high-performance FA-conjugated AuNCs@SiO2 nanoprobes can target in vivo gastric cancer cells, can be used for fluorescent and CT dual-mode imaging, and may own great potential in applications such as targeted dual-mode imaging of in vivo early gastric cancer and other tumors with FR positive expression in near future.
Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src
Authors: Xie Xi , Lan Tian , Chang Xiuting , Huang Kaipeng , Huang Juan , Wang Shaogui , Chen Cheng , Shen Xiaoyan , Liu Peiqing , Huang Heqing
Published: May 2013

Background

Nuclear factor kappa-B (NF-κB) signalling plays an important role in diabetic nephropathy. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. The aim of the current study was to investigate the role of Cx43 in the activation of NF-κB induced by high glucose in glomerular mesangial cells (GMCs) and to determine whether c-Src is involved in this process.

Results

We found that downregulation of Cx43 expression induced by high glucose activated NF-κB in GMCs. Orverexpression of Cx43 attenuated NF-κB p65 nuclear translocation induced by high glucose. High glucose inhibited the interaction between Cx43 and c-Src, and enhanced the interaction between c-Src and IκB-α. PP2, a c-Src inhibitor, also inhibited the tyrosine phosphorylation of IκB-α and NF-κB p65 nuclear translocation induced by high glucose. Furthermore, overexpression of Cx43 or inhibition of c-Src attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta 1 (TGF-β1) and fibronectin (FN) expression induced by high glucose.

Conclusions

In conclusion, downregulation of Cx43 in GMCs induced by high glucose activates c-Src, which in turn promotes interaction between c-Src and IκB-α and contributes to NF-κB activation in GMCs, leading to renal inflammation.
Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways
Authors: Su Yajuan , Gao Lingjuan , Teng Lichen , Wang Ying , Cui Jialin , Peng Shiyun , Fu Songbin
Published: May 2013

Background

Endothelial progenitor cells (EPCs) contribute to tumor angiogenesis and growth. We previously reported that over-expression of an inhibitor of DNA binding/differentiation 1 (Id1) in EPCs can enhance EPC proliferation, migration, and adhesion. In this study, we investigated the role of Id1 in EPC angiogenesis in patients with ovarian cancer and the underlying signaling pathway.

Methods

Circulating EPCs from 22 patients with ovarian cancer and 15 healthy control subjects were cultured. Id1 and matrix metalloproteinase-2 (MMP-2) expression were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. EPC angiogenesis was detected by tube formation assays. Double-stranded DNA containing the interference sequences was synthesized according to the structure of a pGCSIL-GFP viral vector and then inserted into a linearized vector. Positive clones were identified as lentiviral vectors that expressed human Id1 short hairpin RNA (shRNA).

Results

Id1 and MMP-2 expression were increased in EPCs freshly isolated from ovarian cancer patients compared to those obtained from healthy subjects. shRNA-mediated Id1 down-regulation substantially reduced EPC angiogenesis and MMP-2 expression. Importantly, transfection of EPCs with Id1 in vitro induced phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of MMP-2 via NF-κB. Blockage of both pathways by specific inhibitors (LY294002 and PDTC, respectively) abrogated Id1-enhanced EPC angiogenesis.

Conclusions

Id1 can enhance EPC angiogenesis in ovarian cancer, which is mainly mediated by the PI3K/Akt and NF-κB/MMP-2 signaling pathways. Id1 and its downstream effectors are potential targets for treatment of ovarian cancer because of their contribution to angiogenesis.
Region-of-interest determination and bit-rate conversion for H.264 video transcoding
Authors: Huang Shu-Fen , Chen Mei-Juan , Tai Kuang-Han , Li Mian-Shiuan
Published: May 2013

This paper presents a video bit-rate transcoder for baseline profile in H.264/AVC standard to fit the available channel bandwidth for the client when transmitting video bit-streams via communication channels. To maintain visual quality for low bit-rate video efficiently, this study analyzes the decoded information in the transcoder and proposes a Bayesian theorem-based region-of-interest (ROI) determination algorithm. In addition, a curve fitting scheme is employed to find the models of video bit-rate conversion. The transcoded video will conform to the target bit-rate by re-quantization according to our proposed models. After integrating the ROI detection method and the bit-rate transcoding models, the ROI-based transcoder allocates more coding bits to ROI regions and reduces the complexity of the re-encoding procedure for non-ROI regions. Hence, it not only keeps the coding quality but improves the efficiency of the video transcoding for low target bit-rates and makes the real-time transcoding more practical. Experimental results show that the proposed framework gets significantly better visual quality.
Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial
Authors: Hajek Peter , Smith Katie Myers , Dhanji Al-Rehan , McRobbie Hayden
Published: May 2013

Background

Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomised controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates.

Methods

117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or varenicline plus nicotine patch (15 mg/16 hour). Varenicline use commenced one week prior to the target quit date (TQD), patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD. Medication use and smoking status were established at 1, 4 and 12 weeks. Participants lost to follow-up were included as continuing smokers.

Results

92% of participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse effects. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 week and 4 weeks post-TQD (69% vs 59%, p=0.28 and 60% vs 59%, p=0.91, in the nicotine patch and placebo patch arm, respectively), or self reported abstinence rates at 12 weeks (36% vs. 29%, p=0.39, NS).

Conclusions

The efficacy of varenicline was not enhanced by the addition of nicotine patches, although further trials would be useful to exclude the possibility of type II error.

Trial Registration

Clinicaltrials.gov Registration Number: NCT01184664
U1snRNP-mediated suppression of polyadenylation in conjunction with the RNA structure controls poly (A) site selection in foamy viruses
Authors: Schrom Eva-Maria , Moschall Rebecca , Hartl Maximilian J , Weitner Helena , Fecher David , Langemeier Jörg , Bohne Jens , Wöhrl Birgitta M , Bodem Jochen
Published: May 2013

Background

During reverse transcription, retroviruses duplicate the long terminal repeats (LTRs). These identical LTRs carry both promoter regions and functional polyadenylation sites. To express full-length transcripts, retroviruses have to suppress polyadenylation in the 5′LTR and activate polyadenylation in the 3′LTR. Foamy viruses have a unique LTR structure with respect to the location of the major splice donor (MSD), which is located upstream of the polyadenylation signal.

Results

Here, we describe the mechanisms of foamy viruses regulating polyadenylation. We show that binding of the U1 small nuclear ribonucleoprotein (U1snRNP) to the MSD suppresses polyadenylation at the 5′LTR. In contrast, polyadenylation at the 3′LTR is achieved by adoption of a different RNA structure at the MSD region, which blocks U1snRNP binding and furthers RNA cleavage and subsequent polyadenylation.

Conclusion

Recently, it was shown that U1snRNP is able to suppress the usage of intronic cryptic polyadenylation sites in the cellular genome. Foamy viruses take advantage of this surveillance mechanism to suppress premature polyadenylation at the 5’end of their RNA. At the 3’end, Foamy viruses use a secondary structure to presumably block access of U1snRNP and thereby activate polyadenylation at the end of the genome. Our data reveal a contribution of U1snRNP to cellular polyadenylation site selection and to the regulation of gene expression.
Evidence of association between hepatitis C virus genotype 2b and nosocomial transmissions in hemodialysis centers from southern Brazil
Authors: da Silva Naylê Maria Oliveira , Germano Fabiana Nunes , Mendoza-Sassi Raul Andres , Seuánez Hector Nicolas , Soares Marcelo Alves , de Martinez Ana Maria Barral
Published: May 2013

Background

Hepatitis C virus infection is a serious public health problem. Hemodialysis is considered one of the main risk factors of HCV infection, due to several invasive medical procedures and potential nosocomial transmission that patients with chronic renal failure (CRF) are continuously submitted. The aims of this study were to determine the prevalence of HCV and its genotypes in patients with CRF in hemodialysis units in southern Brazil.

Methods

Demographic data and risk factors for HCV transmission were collected and analyzed. These data were obtained from patients undergoing hemodialysis treatment from January 2009 to August 2010, on two dialysis units of Rio Grande, southern Brazil. Genotyping was carried out by sequencing analysis of HCV NS5b, core-E1 junction and 5′UTR genomic regions.

Results

One hundred fifty-nine patients under regular hemodialysis treatment were studied. HCV prevalence was 23.3%. HCV-infected patients had been on dialysis treatment for 91.9 months, a more prolonged period compared to HCV-negative patients (p = 0.001). While HCV genotypes 1b and 3a were identified as the most frequent strains, a surprisingly high proportion of genotype 2b was observed among patients in one of the dialysis centers compared to the general HCV-infected population of the same area. Hemodialysis treatment exposure time and healthcare working were associated with HCV infection.

Conclusions

Besides the efforts to minimize nosocomial transmission of HCV, some events of transmission are still evidenced in dialysis units.
Initial diagnosis of Wegener’s granulomatosis mimicking severe ulcerative colitis: a case report
Authors: Timmermann Sonja , Perez Bouza Alberto , Junge Karsten , Neumann Ulf P , Binnebösel Marcel
Published: May 2013

Introduction

We describe the case of a woman with an unusual presentation of Wegener’s granulomatosis.

Case presentation

A 20-year old Caucasian woman presented with the principal feature of a pancolonic, superficial microulceration mimicking severe ulcerative colitis. Our patient was refractory to therapy and had persisting signs of septic shock as well as being at risk of perforation, so we performed a subtotal colectomy and a cholecystectomy due to the incipient necrosis of her gallbladder. Histologic analysis of her colon showed multiple superficial microulcera of the mucosa, lamina propria mucosae and, to a lesser extent, the lamina submucosa. The medium-sized arteries and arterioles of her entire colon, appendix and gallbladder showed acute vasculitic changes with fibrinoid necrosis of the walls and diffuse infiltration with neutrophil granulocytes, accompanied by a strong perivascular histiocyte-rich and partially granulomatous reaction. These findings strongly suggested an autoimmune multisystem disease like Wegener’s granulomatosis or microscopic polyangiitis. A diagnosis of Wegener’s granulomatosis was confirmed by the results of serologic antibody tests: her cytoplasmic antineutrophil cytoplasmic antibody titer was considerably elevated at 1:2560 specific for subclass proteinase 3 (>200kU/L). After the histopathological diagnosis and serological tests, immunosuppression with high doses of corticosteroids and plasmapheresis was started.

Conclusion

In critically ill patients with severe, therapy-refractory ulcerative colitis, Wegener´s granulomatosis should be considered and serologic antibody testing should be performed.
HPV Status and second primary tumours in Oropharyngeal Squamous Cell Carcinoma
Authors: Xu Caroline C , Biron Vincent L , Puttagunta Lakshmi , Seikaly Hadi
Published: May 2013

Introductions

The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCCs) is rising in developed nations. Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer.

Objective

The purpose of this study was to evaluate the rate of second primary tumors and the diagnostic yield of field cancerization work up in the upper aerodigestive tract in patients with HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma.

Design

Retrospective review.

Setting

Tertiary cancer care centers in Alberta.

Methods

Retrospective review of 406 patients diagnosed with OPSCC in Alberta between 2005 and 2009. HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16.

Main outcome measures

Primary outcome: incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC. Secondary outcomes: diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients.

Results

The overall rate of SPTs was 7.4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02).

Conclusions

Patients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways.
Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
Authors: Cheng Javelin C , McBrayer Samuel K , Coarfa Cristian , Dalva-Aydemir Sevim , Gunaratne Preethi H , Carpten John D , Keats Jonathan K , Rosen Steven T , Shanmugam Mala
Published: May 2013

Background

Multiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4, consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates, proliferative capacity, and viability. The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells.

Findings

We have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect. AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation, known to be required for inactivation of AS160 Rab-GAP activity. Importantly, we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines. Furthermore, we demonstrate that ectopic expression of a full-length, phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence, which is characteristic of MM cells.

Conclusions

This is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer. Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease.
Characterizing and measuring bias in sequence data
Authors: Ross Michael G , Russ Carsten , Costello Maura , Hollinger Andrew , Lennon Niall J , Hegarty Ryan , Nusbaum Chad , Jaffe David B
Published: May 2013

Background

DNA sequencing technologies deviate from the ideal uniform distribution of reads. These biases impair scientific and medical applications. Accordingly, we have developed computational methods for discovering, describing and measuring bias.

Results

We applied these methods to the Illumina, Ion Torrent, Pacific Biosciences and Complete Genomics sequencing platforms, using data from human and from a set of microbes with diverse base compositions. As in previous work, library construction conditions significantly influence sequencing bias. Pacific Biosciences coverage levels are the least biased, followed by Illumina, although all technologies exhibit error-rate biases in high- and low-GC regions and at long homopolymer runs. The GC-rich regions prone to low coverage include a number of human promoters, so we therefore catalog 1,000 that were exceptionally resistant to sequencing. Our results indicate that combining data from two technologies can reduce coverage bias if the biases in the component technologies are complementary and of similar magnitude. Analysis of Illumina data representing 120-fold coverage of a well-studied human sample reveals that 0.20% of the autosomal genome was covered at less than 10% of the genome-wide average. Excluding locations that were similar to known bias motifs or likely due to sample-reference variations left only 0.045% of the autosomal genome with unexplained poor coverage.

Conclusions

The assays presented in this paper provide a comprehensive view of sequencing bias, which can be used to drive laboratory improvements and to monitor production processes. Development guided by these assays should result in improved genome assemblies and better coverage of biologically important loci.
Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy
Authors: Demetri George D. , Chawla Sant P. , Ray-Coquard Isabelle , Le Cesne Axel , Staddon Arthur P. , Milhem Mohammed M. , Penel Nicolas , Riedel Richard F. , Bui-Nguyen Binh , Cranmer Lee D. , Reichardt Peter , Bompas Emmanuelle , Alcindor Thierry , Rushing Daniel , Song Yang , Lee Ruey-min , Ebbinghaus Scot , Eid Joseph E. , Loewy John W. , Haluska Frank G. , Dodion Pierre F. , Blay Jean-Yves
Published: May 2013

Purpose

Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas.

Patients and Methods

Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability.

Results

A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%).

Conclusion

Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.
Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium
Authors: Zwaan C. Michel , Rizzari Carmelo , Mechinaud Francoise , Lancaster Donna L. , Lehrnbecher Thomas , van der Velden Vincent H.J. , Beverloo B. Berna , den Boer Monique L. , Pieters Rob , Reinhardt Dirk , Dworzak Michael , Rosenberg Julie , Manos George , Agrawal Shruti , Strauss Lewis , Baruchel André , Kearns Pamela R.
Published: May 2013

Purpose

Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients.

Patients and Methods

Escalating once-daily dasatinib doses (60 to 120 mg/m2) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)–positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).

Results

Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).

Conclusion

Dasatinib 60 mg/m2and 80 mg/m2once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
Research Resource: Preovulatory LH Surge Effects on Follicular Theca and Granulosa Transcriptomes
Authors: Christenson Lane K. , Gunewardena Sumedha , Hong Xiaoman , Spitschak Marion , Baufeld Anja , Vanselow Jens
Published: May 2013

The molecular mechanisms that regulate the pivotal transformation processes observed in the follicular wall following the preovulatory LH surge, are still not established, particularly for cells of the thecal layer. To elucidate thecal cell (TC) and granulosa cell (GC) type-specific biologic functions and signaling pathways, large dominant bovine follicles were collected before and 21 hours after an exogenous GnRH-induced LH surge. Antral GCs (aGCs; aspirated by follicular puncture) and membrane-associated GCs (mGCs; scraped from the follicular wall) were compared with TC expression profiles determined by mRNA microarrays. Of the approximately 11 000 total genes expressed in the periovulatory follicle, only 2% of thecal vs 25% of the granulosa genes changed in response to the LH surge. The majority of the 203 LH-regulated thecal genes were also LH regulated in GCs, leaving a total of 57 genes as LH-regulated TC-specific genes. Of the 57 thecal-specific LH-regulated genes, 74% were down-regulated including CYP17A1 and NR5A1, whereas most other genes are being identified for the first time within theca. Many of the newly identified up-regulated thecal genes (eg, PTX3, RND3, PPP4R4) were also up-regulated in granulosa. Minimal expression differences were observed between aGCs and mGCs; however, transcripts encoding extracellular proteins (NID2) and matrix modulators (ADAMTS1, SASH1) dominated these differences. We also identified large numbers of unknown LH-regulated GC genes and discuss their putative roles in ovarian function. This Research Resource provides an easy-to-access global evaluation of LH regulation in TCs and GCs that implicates numerous molecular pathways heretofore unknown within the follicle.
The mammalian germline as a pluripotency cycle
Authors: Leitch Harry G. , Smith Austin
Published: May 2013

Naive pluripotency refers to the capacity of single cells in regulative embryos to engender all somatic and germline cell types. Only germ cells – conventionally considered to be unipotent – can naturally re-acquire pluripotency, by cycling through fertilisation. Furthermore, primordial germ cells express, and appear to be functionally dependent upon, transcription factors that characterise the pluripotent state. We hypothesise that germ cells require pluripotency factors to control a de-restricted epigenome. Consequently, they harbour latent potential, as manifested in teratocarcinogenesis or direct conversion into pluripotent stem cells in vitro. Thus, we suggest that there exists an unbroken cycle of pluripotency, naive in the early epiblast and latent in the germline, that is sustained by a shared transcription factor network.
Lysosomal cell death at a glance
Authors: Aits Sonja , Jäättelä Marja
Published: May 2013

Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called “lysosomal cell death”. This form of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream mechanisms that lead to lysosomal membrane permeabilization.
Limits to sustained energy intake. XVI. Body temperature and physical activity of female mice during pregnancy
Authors: Gamo Yuko , Bernard Amelie , Mitchell Sharon E. , Hambly Catherine , Al Jothery Aqeel , Vaanholt Lobke M. , Król Elzbieta , Speakman John R.
Published: May 2013

Lactation is the most energy-demanding phase of mammalian reproduction, and lactation performance may be affected by events during pregnancy. For example, food intake may be limited in late pregnancy by competition for space in the abdomen between the alimentary tract and fetuses. Hence, females may need to compensate their energy budgets during pregnancy by reducing activity and lowering body temperature. We explored the relationships between energy intake, body mass, body temperature and physical activity throughout pregnancy in the MF1 mouse. Food intake and body mass of 26 females were recorded daily throughout pregnancy. Body temperature and physical activity were monitored every minute for 23 h a day by implanted transmitters. Body temperature and physical activity declined as pregnancy advanced, while energy intake and body mass increased. Compared with a pre-mating baseline period, mice increased energy intake by 56% in late pregnancy. Although body temperature declined as pregnancy progressed, this served mostly to reverse an increase between baseline and early pregnancy. Reduced physical activity may compensate the energy budget of pregnant mice but body temperature changes do not. Over the last 3 days of pregnancy, food intake declined. Individual variation in energy intake in the last phase of pregnancy was positively related to litter size at birth. As there was no association between the increase in body mass and the decline in intake, we suggest the decline was not caused by competition for abdominal space. These data suggest overall reproductive performance is probably not constrained by events during pregnancy.
Limits to sustained energy intake. XVIII. Energy intake and reproductive output during lactation in Swiss mice raising small litters
Authors: Zhao Zhi-Jun , Song De-Guang , Su Zhen-Cheng , Wei Wen-Bo , Liu Xian-Bin , Speakman John R.
Published: May 2013

Limits to sustained energy intake (SusEI) during lactation in Swiss mice have been suggested to reflect the secretory capacity of the mammary glands. However, an alternative explanation is that milk production and food intake are regulated to match the limited growth capacity of the offspring. In the present study, female Swiss mice were experimentally manipulated in two ways – litter sizes were adjusted to be between 1 and 9 pups and mice were exposed to either warm (21°C) or cold (5°C) conditions from day 10 of lactation. Energy intake, number of pups and litter mass, milk energy output (MEO), thermogenesis, mass of the mammary glands and brown adipose tissue cytochrome c oxidase activity of the mothers were measured. At 21 and 5°C, pup mass at weaning was almost independent of litter size. Positive correlations were observed between the number of pups, litter mass, asymptotic food intake and MEO. These data were consistent with the suggestion that in small litters, pup requirements may be the major factor limiting milk production. Pups raised at 5°C had significantly lower body masses than those raised at 21°C. This was despite the fact that milk production and energy intake at the same litter sizes were both substantially higher in females raising pups at 5°C. This suggests that pup growth capacity is lower in the cold, perhaps due to pups allocating ingested energy to fuel thermogenesis. Differences in observed levels of milk production under different conditions may then reflect a complex interplay between factors limiting maternal performance (peripheral limitation and heat dissipation: generally better when it is cooler) and factors influencing maximum pup growth (litter size and temperature: generally better when it is hotter), and may together result in an optimal temperature favouring reproduction.