bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive mutation in nuclear export protein allows stable transgene expression in a chimaeric influenza A virus vector
Authors: Kuznetsova Irina , Shurygina Anna-Polina , Wolf Brigitte , Wolschek Markus , Enzmann Florian , Sansyzbay Abylay , Khairullin Berik , Sandybayev Nurlan , Stukova Marina , Kiselev Oleg , Egorov Andrej , Bergmann Michael
Published: November 2013

The development of influenza virus vectors with long insertions of foreign sequences remains difficult due to the small size and instable nature of the virus. Here, we used the influenza virus inherent property of self-optimization to generate a vector stably expressing long transgenes from the NS1 protein ORF. This was achieved by continuous selection of bright fluorescent plaques of a GFP-expressing vector during multiple passages in mouse B16f1 cells. The newly generated vector acquired stability in IFN-competent cell lines and in vivo in murine lungs. Although improved vector fitness was associated with the appearance of four coding mutations in the polymerase (PB2), haemagglutinin and non-structural (NS) segments, the stability of the transgene expression was dependent primarily on the single mutation Q20R in the nuclear export protein (NEP). Importantly, a longer insert, such as a cassette of 1299 nt encoding two Mycobacterium tuberculosis Esat6 and Ag85A proteins, could substitute for the GFP transgene. Thus, the inherent property of the influenza virus to adapt can also be used to adjust a vector backbone to give stable expression of long transgenes.
Genomic and transcriptomic plasticity in treatment-naïve ovarian cancer
Authors: Hoogstraat Marlous , de Pagter Mirjam S. , Cirkel Geert A. , van Roosmalen Markus J. , Harkins Timothy T. , Duran Karen , Kreeftmeijer Jennifer , Renkens Ivo , Witteveen Petronella O. , Lee Clarence C. , Nijman Isaac J. , Guy Tanisha , van ’t Slot Ruben , Jonges Trudy N. , Lolkema Martijn P. , Koudijs Marco J. , Zweemer Ronald P. , Voest Emile E. , Cuppen Edwin , Kloosterman Wigard P.
Published: November 2013

Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A, and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes, and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed up-regulation of key cancer pathways including WNT, integrin, chemokine, and Hedgehog signaling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multilevel tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in-frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.
City of Rents: The limits to the Barcelona model of urban competitiveness
Authors: Charnock Greig , Purcell Thomas F. , Ribera‐Fumaz Ramon
Published: November 2013

The turn towards the knowledge‐based economy and creative strategies to enhance urban competitiveness within it has been well documented. Yet too little has been said to date about the transformation of land use for new productive activities, and the contradictions inherent to this process. Our case study is Barcelona, an erstwhile ‘model’ for urban regeneration which has sought to transform itself into a global knowledge city since 2000. Through the lens of Marxian value theory, and Harvey's writing on urban monopoly rents especially, we show how the 22@Barcelona project — conceived with received wisdom about the determinants of urban knowledge‐based competitiveness in mind — amounted to an exercise in the capture of monopoly rents, driven by the compulsion of public sector institutions, financiers and developers to pursue rental profit‐maximizing opportunities through the mobilization of land as a financial asset.
Inheritance patterns of secondary symbionts during sexual reproduction of pea aphid biotypes
Authors: Peccoud Jean , Bonhomme Joël , Mahéo Frédérique , de la Huerta Manon , Cosson Olivier , Simon Jean‐Christophe
Published: November 2013

Herbivorous insects frequently harbor bacterial symbionts that affect their ecology and evolution. Aphids host the obligatory endosymbiont Buchnera, which is required for reproduction, together with facultative symbionts whose frequencies vary across aphid populations. These maternally transmitted secondary symbionts have been particularly studied in the pea aphid, Acyrthosiphon pisum, which harbors at least 8 distinct bacterial species (not counting Buchnera) having environmentally dependent effects on host fitness. In particular, these symbiont species are associated with pea aphid populations feeding on specific plants. Although they are maternally inherited, these bacteria are occasionally transferred across insect lineages. One mechanism of such nonmaternal transfer is paternal transmission to the progeny during sexual reproduction. To date, transmission of secondary symbionts during sexual reproduction of aphids has been investigated in only a handful of aphid lineages and 3 symbiont species. To better characterize this process, we investigated inheritance patterns of 7 symbiont species during sexual reproduction of pea aphids through a crossing experiment involving 49 clones belonging to 9 host‐specialized biotypes, and 117 crosses. Symbiont species in the progeny were detected with diagnostic qualitative PCR at the fundatrix stage hatching from eggs and in later parthenogenetic generations. We found no confirmed case of paternal transmission of symbionts to the progeny, and we observed that maternal transmission of a particular symbiont species (Serratia symbiotica) was quite inefficient. We discuss these observations in respect to the ecology of the pea aphid.
Comparison of the potential rate of population increase of brown and green color morphs of Sitobion avenae (Homoptera: Aphididae) on barley infected and uninfected with Barley yellow dwarf virus
Authors: Hu Zu‐Qing , Zhao Hui‐Yan , Thieme Thomas
Published: November 2013

Life tables of brown and green color morphs of the English grain aphid, Sitobion avenae (Fabricius) reared on barley under laboratory conditions at 20 ± 1°C, 65% ± 5% relative humidity and a photoperiod of 16 : 8 h (L : D) were compared. The plants were either: (i) infected with the Barley yellow dwarf virus (BYDV); (ii) not infected with virus but previously infested with aphids; or (iii) healthy barley plants, which were not previously infested with aphids. Generally, both color morphs of S. avenae performed significantly better when fed on BYDV‐infected plants than on plants that were virus free but had either not been or had been previously infested with aphids. Furthermore, when fed on BYDV‐infected plants, green S. avenae developed significantly faster and had a significantly shorter reproductive period than the brown color morph. There were no significant differences in this respect between the two color morphs of S. avenae when they were reared on virus‐free plants that either had been or not been previously infested with aphids. These results indicate that barley infected with BYDV is a more favorable host plant than uninfected barley for both the color morphs of S. avenae tested, particularly the green color morph.
Predictors of dietary change among those who successfully lost weight in phase I of the Weight Loss Maintenance Trial
Authors: McVay Megan A. , Myers Valerie H. , Vollmer William M. , Coughlin Janelle W. , Champagne Catherine M. , Dalcin Arlene T. , Funk Kristine L. , Hollis Jack F. , Jerome Gerald J. , Samuel‐Hodge Carmen D. , Stevens Victor J. , Svetkey Laura P. , Brantley Phillip J.
Published: November 2013

Aim

Dietary changes occurring during weight loss interventions can vary. The present study tested if pretreatment psychosocial, dietary and demographic factors were associated with changes in fat intake and fruit and vegetable intake during a weight loss intervention.

Methods

This analysis includes participants who lost at least four kilograms during the initial six month weight loss phase (phase I) of the Weight Loss Maintenance Trial, a group format behavioural intervention emphasising a low‐fat diet and increased physical activity. Multiple linear regression was used to determine associations between pretreatment psychosocial, dietary, physical activity, and demographic variables and changes from pretreatment to six months in fat intake and fruit and vegetable intake.

Results

Participants (n = 1032) were 63.4% female, 62.4% non‐African American, and had a mean age of 55.6 and BMI of 34.1 kg/m2. Being African American (P < 0.0001) and higher baseline kilojoule intake (P < 0.01) were associated with smaller reductions in fat intake. Being African American (p < 0.001) and older age (P = 0.02) were associated with smaller increases in fruit and vegetable intake, whereas a history of 10 or more past weight loss episodes of at least 10 lb (4.5 kg; P < 0.01) was associated with greater increases.

Conclusions

Few psychosocial factors examined contributed to variability in dietary change. Even when achieving meaningful weight losses during a behavioural weight loss intervention, African Americans may make fewer beneficial changes in fat and fruit and vegetable intake than non‐African Americans.
Aspirational competency expectations for public health nutritionists in Australia: A consensus study
Authors: Hughes Roger , Begley Andrea , Yeatman Heather
Published: November 2013

Aim

To assess consensus among public health nutrition (PHN) workforce development stakeholders on the competencies required for effective PHN practice in the Australian workforce context.

Methods

A modified Delphi study involving two iterative survey rounds among an expert panel of 33 Australian PHN workforce development stakeholders. Surveys tested panellist ratings (essential, useful, irrelevant) of a listing of 143 competency elements derived from the literature and existing competency standards, across two survey rounds, with feedback between rounds. An arbitrary consensus cut‐off of 67% was applied with <10% change between rounds or 100% agreement interpreted as agreement stability.

Results

A total of 109 competency elements from the total list of 143 were rated as essential above the consensus cut‐off, representing 76% of the original list. Thirty‐three (33) elements were rated as essential by 100% of panellists. Approximately 90% or more of the competency elements tested were retained using the 67% cut‐off across nutrition science, nutrition communication, professional communication, capacity building and intervention management competency units. Competency elements rated as essential beyond the consensus cut‐off concentrated in the practice competency units of nutrition assessment, monitoring and surveillance, capacity building, and intervention management.

Conclusions

The results provide an empirical basis for future nutrition curriculum renewal and workforce development innovations and challenge the assumption that existing dietetic workforce preparation based on meeting entry‐level competencies is adequate for community and PHN practice.
Inhibition of α‐glucosidase and glucose intestinal absorption by Thymelaea hirsuta fractions (毛花瑞香成分对α‐糖甙酶以及肠道葡萄糖吸收的抑制作用)
Authors: Abid Sanae , Lekchiri Abdenbi , Mekhfi Hassane , Ziyyat Abderrahim , Legssyer Abdekhaleq , Aziz Mohamed , Bnouham Mohamed
Published: November 2013

Background

Thymelaea hirsuta (L.) Endl. (Thymelaeaceae) is a medicinal plant used in Morocco to treat diabetes. In previous studies T. hirsuta has shown a potent antihyperglycemic effect. Our aim was to study the effect of the plant on α‐glucosidase inhibition and intestinal glucose absorption.

Methods

Five fractions of T. hirsuta were tested, in vitro, in vivo and, in situ, to elucidate the inhibition of α‐glucosidase and intestinal glucose uptake.

Results

The fractions induced, in vitro, a significant inhibition of α‐glucosidase. The ethyl acetate fraction (EATh) had high activity and its inhibition mode was non‐competitive. The EATh at 50 and 100 mg/kg doses, decreased significantly, in vivo, the postprandial hyperglycemia after sucrose loading in normal and diabetic mice. Moreover, 50 mg/kg of EATh significantly decreased intestinal glucose uptake, in situ, in rats.

Conclusion

The antihyperglycemic effect of T. hirsuta can be explained, in part, by the inhibition of intestinal α‐glucosidase and intestinal glucose absorption.
The Influence of Status on Group Drinking by Young Adults: A Survey of Natural Drinking Groups on Their Way To and From Bars
Authors: Dumas Tara M. , Wells Samantha , Flynn Andrea , Lange James E. , Graham Kathryn
Published: November 2013

Background

Young people's social standing among friends and peers has been linked to general levels of drinking and has been shown to influence others' drinking. We extend previous research by examining young adults' status within their natural‐occurring drinking groups as a predictor of their subsequent alcohol consumption and encouragement of group members' alcohol consumption during a night out at licensed drinking establishments, a salient context for heavy drinking and alcohol‐related risk among young adults.

Methods

We recruited same‐sex young adult drinking groups (n = 104 groups; 63 all‐male; average group size = 3.4 members; Mage = 21.86) on their way to drinking establishments to complete a survey—containing measures of member‐nominated within‐group status, likeability, and self‐reported alcohol consumption—and a breathalyzer test. At the end of the evening, participants completed the same alcohol consumption measures and were asked to nominate group members who encouraged other members to drink that night.

Results

Multilevel analysis revealed that higher‐status members engaged in the most alcohol consumption (via both self‐report and breathalyzer) but in heavier drinking groups only. Higher‐status members also encouraged the most alcohol consumed by others, regardless of levels of group drinking. Further, even though being liked by one's peers was positively related to intoxication that night, it did not account for the significant relationship between within‐group status and drinking.

Conclusions

Results suggest that peer‐related prevention programs for young adults' problem drinking may benefit from focusing on the structure and dynamic of young people's drinking groups. Also, programs targeting peer norms may be more successful if they incorporate status‐related issues.
The evolving role of a gynaecologic oncologist in a tertiary hospital
Authors: Acton Jade , Leung Yee , Tan Jason , Salfinger Stuart
Published: November 2013

Introduction

Whilst the prime role of a gynaecologic oncologist is the comprehensive management of women with a gynaecologic cancer, their surgical skills are increasingly utilised for general gynaecological and obstetric surgery. Within tertiary centres, there is increasing provision of support by gynaecologic oncologists for both emergency and complex elective cases.

Aim

The aim of the study was to investigate and define the expanding role of the gynaecologic oncologist within obstetrics and gynaecology.

Method

A retrospective analysis of all nongynaecological oncology unit cases from 2006 to 2012 which required the presence of a gynaecologic oncologist in the operating theatre.

Results

A wide variety of cases that required the involvement of a gynaecologic oncologist were identified. These ranged from complications such as bowel injuries and haemorrhage to gynaecological surgeries in complicated patients, and obstetric patients with placenta accreta and intra‐operative diagnosis of unexpected malignancy.

Conclusion

The role of the gynaecologic oncologist within a tertiary centre is expanding to include the provision of support to general gynaecologists and obstetricians. There is increasing utilisation of the gynaecologic oncologist whereby their attendance is often pre‐arranged prior to the surgery. However, emergency cases requiring their assistance are not uncommon.
Behavior of Lyophilized Biological Valves in a Chronic Animal Model
Authors: Maizato Marina J.S. , Taniguchi Fabio P. , Ambar Rafael F. , Pitombo Ronaldo N.M. , Leirner Adolfo A. , Cestari Idágene A. , Stolf Noedir A.G.
Published: November 2013

Glutaraldehyde is used in order to improve the mechanical and immunogenic properties of biological tissues, such as bovine pericardium membranes, used to manufacture heart valve bioprostheses. Lyophilization, also known as freeze‐drying, preserves biological material without damage by freezing the water content and removing ice by sublimation. Through this process, dehydrated products of high quality may be obtained; also, the material may be easily handled. The lyophilization process reduces aldehyde residues in biological tissue previously treated with glutaraldehyde, thus promoting reduction of cytotoxicity, increasing resistance to inflammation, and possibly decreasing the potential for tissue calcification. The objective of this study was to chronically evaluate the calcification of bovine pericardium heart valve prostheses, previously lyophilized or not, in an animal model. Six‐month‐old sheep received implants of lyophilized and unlyophilized heart valve prostheses in the pulmonary position with right bypass. The study followed 16 animals for a period of 90 days. Right ventricle–pulmonary artery (RV/PA) transvalvular pressure gradient was evaluated before and immediately after implantation and before explantation, as were tissue calcium, inflammation intensity, and thrombosis and pannus formation. The t‐test was used for statistical analysis. Twelve animals survived to the end of the experiment, but one of the animals in the control group had endocarditis and was excluded from the data. Four animals died early. The mean RV/PA gradient on implantation was 2.0 ± 1.6 mm Hg in the control group and 6.2 ± 4.1 mm Hg in the lyophilized group (P = 0.064). This mean gradient increased at explantation to 7.7 ± 3.9 mm Hg and 8.6 ± 5.8 mm Hg, respectively (P = 0.777). The average calcium content in the tissue leaflets after 3 months was 21.6 ± 39.1 mg Ca2+/g dry weight in the control group, compared with an average content of 41.2 ± 46.9 mg Ca2+/g dry weight in the lyophilized group (P = 0.478). In this experimental study there was no reduction of calcification after lyophilization. However, histological analysis showed less inflammation over the lyophilized tissue when compared with the control.
Hjalmar Schiøtz, the great Norwegian innovator and his ophthalmoscope
Authors: Keeler C. Richard , Helland Magne , Albert Daniel M.
Published: November 2013

Recently, the authors encountered an intriguing and largely incomplete ophthalmoscope. The quest to identify and restore it led to a re‐evaluation of the evolution of the modern‐day ophthalmoscope and a re‐examination of the life and contributions of its inventor, the Norwegian ophthalmologist Hjalmar August Schiøtz.
Structural and floristic diversity of mixed tropical rain forest in New Caledonia: new data from the New Caledonian Plant Inventory and Permanent Plot Network (NC‐PIPPN)
Authors: Ibanez Thomas , Munzinger Jérôme , Dagostini Gilles , Hequet Vanessa , Rigault Frédéric , Jaffré Tanguy , Birnbaum Philippe
Published: November 2013

Aims

To describe the structural and floristic diversity of New Caledonian mixed tropical rain forest and investigate its environmental determinants.

Location

New Caledonia (SW Pacific), a biodiversity hotspot.

Methods

Structural (stem density, basal area) and floristic characteristics (composition, species richness and dissimilarity) were investigated along environmental gradients (elevation, rainfall and slope) on different substrates (ultramafic and non‐ultramafic) through the New Caledonian Plant Inventory and Permanent Plots Network (NC‐PIPPN, 201 plots each measuring 20 m x 20 m).

Results

A total of 28,640 trees (DBH ≥5 cm) belonging to 749 species, 240 genera and 92 families were inventoried in the NC‐PIPPN. The New Caledonian mixed rain forest studied was characterized as having high stem density, basal area and species richness, and many small stems (60% of the trees <10 cm DBH and almost a quarter of species did not exceed this threshold). More than one‐third of the species were rare (i.e. inventoried in less than three plots or represented by fewer than three individuals) in the plot network and floristic dissimilarity was high (Bray–Curtis index >0.70). The presence of ultramafic (UM) and non‐ ultramafic substrates (non‐UM) combined with altitudinal and rainfall gradients were the main drivers of floristic dissimilarity, whereas the effect of geographic distance between the plots was surprisingly low. Floristic dissimilarity was very high between UM and non‐UM substrates from species up to family level. About 75% of the species occurred on a single substrate type. The mixed rain forest on UM and non‐UM substrates differed in floristic composition but not in structure.

Conclusions

NC‐PIPPN proved to be an effective tool for investigating the woody species richness of New Caledonia as containing ca. 46% of its non‐herbaceous species. However, the network's design, and more specifically its small plots, restricts its capacity to capture beta diversity and forest structure. High species richness and floristic dissimilarity confirm that New Caledonian mixed rain forest is exceptionally rich.
A New Algorithm for Weekly Phenprocoumon Dose Variation in a Southern Brazilian Population: Role for CYP2C9, CYP3A4/5 and VKORC1 Genes Polymorphisms
Authors: Botton Mariana R. , Viola Patrícia P. , Bandinelli Eliane , Leiria Tiago L. L. , Rohde Luis E. P. , Hutz Mara H.
Published: November 2013

Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non‐genetic factors. Phenprocoumon metabolism is mediated by CYP2C9 and CYP3A enzymes. Moreover, VKORC1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP3A4 and CYP3A5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of European ancestry, were investigated. Genotypes were determined by allelic discrimination with TaqMan assays. Polymorphisms −1639G>A and 1173C>T in VKORC1 and the presence of CYP2C9*2 and/or CYP2C9*3 are associated with lower doses. On the other hand, 3730G>A in VKORC1 gene is associated with higher doses. No association was found between CYP3A4*1B, CYP3A5*3 and CYP3A5*6 polymorphisms. Among non‐genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and β‐blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm.
Ontogeny of CYP3A and P‐Glycoprotein in the Liver and the Small Intestine of the Göttingen Minipig: An Immunohistochemical Evaluation
Authors: Van Peer Els , Verbueken Evy , Saad Moayad , Casteleyn Christophe , Van Ginneken Chris , Van Cruchten Steven
Published: November 2013

Despite the increasing use of the minipig as a non‐rodent species in general and juvenile toxicity studies, knowledge on their biotransformation processes and their ontogeny is scarce. Such data are prerequisite for the correct interpretation of non‐clinical studies in this species. Therefore, the aim of our investigation was to immunohistochemically document the presence of the drug transporter P‐glycoprotein (Pgp) and the metabolizing cytochrome P450 (CYP) 3A subfamily in the livers (n = 115) and the small intestines (n = 74) of foetal, neonatal, juvenile and adult Göttingen minipigs. Pgp was expressed in the liver in all age groups, whereas its presence in the jejunum was detected from 86 days of gestation onwards. Low expression of CYP3A was detected in the jejunums and livers from foetal and neonatal piglets. During postnatal development, the immunoreactivity for CYP3A increased in both organs. A centrilobular pattern, with a more intense staining for CYP3A of the hepatocytes surrounding the central vein, was noticed in the postnatal livers. In conclusion, the presented data suggest that the intestinal and hepatic ontogeny of P‐glycoprotein and CYP3A in minipigs corresponds to that in man, in which a similar spatio‐temporal expression has been reported.
Meta‐analysis of predictors of favorable employment outcomes among individuals with bipolar disorder
Authors: Tse Samson , Chan Sunny , Ng King Lam , Yatham Lakshmi N
Published: November 2013

Objectives

Although several studies have reported on predictors of employment in individuals with bipolar disorder (BD), the magnitude of the impact of these variables is unclear as no previous studies have estimated the collective effect sizes (ESs). The present meta‐analysis estimated ESs and explored which of these variables are associated with positive employment outcomes.

Methods

We searched for articles published between 2000 and 2011 that reported associations between sociodemographic, clinical, psychosocial, and/or cognitive variables with employment outcomes in BD. Of the 781 articles identified, 22 met the inclusion criteria and were included in the final analysis (n = 6,301). Weighted correlation coefficients (r‐index) were computed as ESs for each of the predictor variables, which were grouped into six categories: cognitive performance, symptomatology, sociodemographic factors, course of illness, clinical variables, and other personal factors. The overall ES (Rw) was estimated by assuming random‐effect models. Sensitivity analyses were also performed to determine the robustness of the findings.

Results

Significant predictors of favorable employment outcomes included: cognitive performance (e.g., verbal memory, Rw = 0.33; executive function, Rw = 0.26), sociodemographic factors (e.g., years of education, Rw = 0.23), course of illness (e.g., number of lifetime psychiatric hospitalizations, Rw = −0.35), symptomatology (e.g., depression, Rw = −0.25), and other personal factors (e.g., personality disorder, Rw = −0.49).

Conclusions

Overall, the cognitive performance and course of illness had larger average ESs than symptomatology or sociodemographic factors on favorable employment outcomes. These findings may help to guide the design of more effective work interventions for people with BD.
Expression of ZAP70 in chronic lymphocytic leukaemia activates NF‐κB signalling
Authors: Pede Valerie , Rombout Ans , Vermeire Jolien , Naessens Evelien , Vanderstraeten Hanne , Philippé Jan , Verhasselt Bruno
Published: November 2013

Chronic lymphocytic leukaemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy‐chain genes (IGHV) and expression of zeta‐associated protein of 70 kDa (ZAP70). The reason why ZAP70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP70 to CLL cells, we show here that expression of ZAP70 in CLL cells leads to increased expression of the nuclear factor (NF)‐κB target genes interleukin‐1β (IL1B), IL6 and IL8 upon BCR triggering. This could be blocked by inhibition of NF‐κB signalling through inhibition of IκB kinases (IKK). Transcriptome analysis identified a NF‐κB RELA signature imposed by ZAP70 expression in BCR‐stimulated CLL cells. We conclude that ZAP70 acts directly as an amplifier of NF‐κB signalling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.
A nomogram including baseline prognostic factors to estimate the activity of second‐line therapy for advanced urothelial carcinoma
Authors: Pond Gregory R. , Agarwal Neeraj , Bellmunt Joaquim , Choueiri Toni K. , Qu Angela , Fougeray Ronan , Vaughn David , James Nicholas D. , Salhi Yacine , Albers Peter , Niegisch Günter , Galsky Matthew D. , Wong Yu‐Ning , Ko Yoo‐Joung , Stadler Walter M. , O'Donnell Peter H. , Sridhar Srikala S. , Vogelzang Nicholas J. , Necchi Andrea , Di Lorenzo Giuseppe , Sternberg Cora N. , Mehta Amitkumar , Sonpavde Guru
Published: November 2013

Objective

To study the impact of the prognostic factors liver metastasis (LM), anaemia (haemoglobin [Hb] <10 g/dL), Eastern Cooperative Oncology Group performance status (ECOG‐PS) ≥1 and time from previous chemotherapy (TFPC) on the activity of second‐line therapy for advanced urothelial carcinoma (UC).

Patients and Methods

Twelve phase II trials evaluating second‐line chemotherapy and/or biological characteristics (n = 748) in patients with progressive disease were pooled.

Progression‐free survival (PFS) was defined as tumour progression or death from any cause.

The PFS rate at 6 months (PFS6) was defined from the date of registration and calculated using the Kaplan–Meier method.

Response rate (RR) was defined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0.

A nomogram predicting PFS6 was constructed using the rms software package in R (http://www.r‐project.org).

Results

Data regarding progression, anaemia, LM, ECOG‐PS and TFPC were available from 570 patients in nine phase II trials.

The overall median PFS was 2.7 months, PFS6 was 22.2% (95% confidence interval 18.8–25.9) and the RR was 17.5% (95% CI: 14.5–20.9%).

For every unit increase in risk group, the hazard of progression in 6 months increased by 41% and the odds of response decreased by 48%.

A nomogram was constructed to predict PFS6 on an individual patient level.

The model was internally validated and was shown to have acceptable calibration performance.

Conclusions

The RR and PFS6 vary as a function of baseline prognostic factors in patients receiving second‐line therapy for advanced UC.

A nomogram incorporating prognostic factors facilitates the evaluation of outcomes across phase II trials enrolling heterogeneous populations and helps select suitable agents for phase III testing.
Effect of a poly(ADP‐ribose) polymerase‐1 inhibitor against esophageal squamous cell carcinoma cell lines
Authors: Nasuno Tomomitsu , Mimaki Sachiyo , Okamoto Makito , Esumi Hiroyasu , Tsuchihara Katsuya
Published: November 2013

Effective molecular target drugs that improve therapeutic efficacy with fewer adverse effects for esophageal cancer are highly anticipated. Poly(ADP‐ribose) polymerase (PARP) inhibitors have been proposed as low‐toxicity agents to treat double strand break (DSB)‐repair defective tumors. Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). We evaluated the effect of a PARP Inhibitor (AZD2281) on the TE‐series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one (TE‐6) was reduced by AZD2281 to the level of DSB repair‐defective Capan‐1 and HCC1937 cells. AZD2281‐induced DNA damage was implied by increases in γ‐H2AX and cell cycle arrest at G2/M phase. The impairment of DSB repair in TE‐6 cells was suggested by a sustained increase in γ‐H2AX levels and the tail moment calculated from a neutral comet assay after X‐ray irradiation. Because the formation of nuclear DSB repair protein foci was impaired in TE‐6 cells, whole‐exome sequencing of these cells was performed to explore the gene mutations that might be responsible. A novel mutation in RNF8, an E3 ligase targeting γ‐H2AX was identified. Consistent with this, polyubiquitination of γ‐H2AX after irradiation was impaired in TE‐6 cells. Thus, AZD2281 induced growth retardation of the DSB repair‐impaired TE‐6 cells. Interestingly, a strong correlation between basal expression levels of γ‐H2AX and sensitivity to AZD2281was observed in the TE‐series cells (R2 = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor‐tractable tumors, further investigation is warranted.
Accuracy of Quantitative Computed Tomography Bone Mineral Density Measurements in Mandibles: A Cadaveric Study
Authors: Miguel‐Sánchez Alfonso , Vilaplana‐Vivo Jaime , Vilaplana‐Vivo Carlos , Vilaplana‐Gómez Juan Ángel , Camacho‐Alonso Fabio
Published: November 2013

Purpose

The aim was to investigate the accuracy of quantitative computed tomography bone mineral density (BMD) measurements in mandibles, comparing measured BMD with calibrated BMD.

Materials and Methods

Seventy mandibles from adult cadavers were used. Twenty tomographic cuts were made in each mandible. In each tomographic cut, a region of interest was located, and the bone density was measured in Hounsfield unit (HU). A polymethyl methacrylate phantom containing four inserts of different predetermined densities (hydroxyapatite 100, 200, 500, and 700 mg/cm3) was used to calculate calibrated bone density. Correlation between measured and calibrated bone densities was calculated.

Results

Mean total correlation between measured and calibrated BMD in the 20 sagittal tomography cuts showed almost perfect positive correlation (r = 0.998, p < .001). However, when average BMD measurements in HU were compared, the measured total BMD (in the 20 sagittal tomography cuts studied) was 54.99 ± 421.59, whereas the total calibrated BMD was 49.28 ± 364.95, with statistically significant difference (p = .001).

Conclusions

There are discrepancies between measured and calibrated BMD; in this sense, a calibrated bone phantom with a predetermined mineral density should be used to determine the exact BMD before dental implants surgery.
Loss of melanocytes in hypopigmented mycosis fungoides: a study of 18 patients
Authors: Furlan Fabricio C. , de Paula Pereira Bruna A. , da Silva Luiz F. , Sanches José A.
Published: November 2013

Background

Hypopigmentation in hypopigmented mycosis fungoides (MF) is thought to result from the action of CD8+ cells on melanocytes. Here, we investigated the immunophenotype and melanocytic markers in hypopigmented MF lesions.

Methods

Specimens of hypopigmented lesions and normal skin from 18 patients with hypopigmented MF and specimens of non‐hypopigmented lesions from 8 patients with classic/conventional MF were subjected to neoplastic immunophenotyping and melanocyte immunostaining with Melan‐A, tyrosinase, stem cell factor receptor (CD117) and microphthalmia‐associated transcription factor (MiTF).

Results

The CD8+ immunophenotype was more common in hypopigmented MF lesions (14/18) than in conventional MF lesions (1/8, p = 0.0033). There was a main effect of specimen type (hypopigmented MF lesion, hypopigmented MF normal skin, conventional MF lesion) on the number of melanocytes stained with Melan‐A (median number/mm basal membrane, 1.97 vs. 4.77 vs. 5.42, respectively, p = 0.0046), tyrosinase (2.19 vs. 4.02 vs. 5.26, p = 0.0114), CD117 (4.29 vs. 7.81 vs. 5.45, p = 0.0064), and MiTF (2.75 vs. 4.43 vs. 4.98, p = 0.005).

Conclusions

These results confirm previous findings of fewer melanocytes and CD117‐positive melanocytes in hypopigmented MF and showed reduced MiTF identification, which is crucial for the function and survival of melanocytes. Thus cytotoxic CD8+ cell action may determine CD117/MiTF dysfunction, causing hypopigmentation.
Role of endoscopic ultrasonography in pancreatic cystic neoplasms: Where do we stand and where will we go?
Authors: Nakai Yousuke , Isayama Hiroyuki , Itoi Takao , Yamamoto Natsuyo , Kogure Hirofumi , Sasaki Takashi , Hirano Kenji , Tada Minoru , Koike Kazuhiko
Published: November 2013

We increasingly encounter pancreatic cystic neoplasms (PCN) in clinical practice and the differential diagnoses vary widely from benign to malignant. There is no ‘one and only’ diagnostic procedure for PCN. Multiple modalities including computed tomography, magnetic resonance imaging, endoscopic retrograde cholangiopancreatography and endoscopic ultrasound (EUS) are widely used, but EUS has the advantage of anatomical proximity to the pancreas and upper gastrointestinal tract. In addition, EUS‐guided fine‐needle aspiration (EUS‐FNA) provides both cytological evaluation and cyst fluid analysis. Although the role of EUS‐FNA for PCN is established, the sensitivity of cytology is low and cyst fluid analysis is only useful for differentiation between mucinous and non‐mucinous cysts. Recently, novel through‐the‐needle imaging under EUS‐FNA, such as confocal laserendomicroscopy, is expected to attribute to a better diagnostic yield. Moreover, feasibility of cyst ablation has been reported and the role of EUS has expanded from diagnosis to treatment. However, clinical impact of cyst ablation in terms of safety, efficacy and cost‐effectiveness should be validated further. In summary, EUS and EUS‐guided intervention does and will play a central role in the management of PCN from surveillance to treatment, but many clinical questions remain unanswered, which warrants well‐designed prospective clinical trials.
Household Saving in China: The Keynesian Hypothesis, Life‐Cycle Hypothesis, and Precautionary Saving Theory
Authors: Liu Shenglong , Hu Angang
Published: November 2013

We test the explanatory powers of Keynesian theory, the life‐cycle hypothesis, and the precautionary saving theory on household saving in China, based on data from 1990 to 2009 from 31 provinces and autonomous regions. The results show that the precautionary saving motivation explains household saving better than Keynesian theory. The study results also highlight the impact of life expectancy on China's household saving.
Regulation of Na+/K+‐ATPase by neuron‐specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons
Authors: Johar Kaid , Priya Anusha , Wong‐Riley Margaret T. T.
Published: November 2013

A major source of energy demand in neurons is the Na+/K+‐ATPase pump that restores the ionic gradient across the plasma membrane subsequent to depolarizing neuronal activity. The energy comes primarily from mitochondrial oxidative metabolism, of which cytochrome c oxidase (COX) is a key enzyme. Recently, we found that all 13 subunits of COX are regulated by specificity (Sp) factors, and that the neuron‐specific Sp4, but not Sp1 or Sp3, regulates the expression of key glutamatergic receptor subunits as well. The present study sought to test our hypothesis that Sp4 also regulates Na+/K+‐ATPase subunit genes in neurons. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutational analysis, over‐expression, and RNA interference studies, we found that Sp4, with minor contributions from Sp1 and Sp3, functionally regulate the Atp1a1, Atp1a3, and Atp1b1 subunit genes of Na+/K+‐ATPase in neurons. Transcripts of all three genes were up‐regulated by depolarizing KCl stimulation and down‐regulated by the impulse blocker tetrodotoxin (TTX), indicating that their expression was activity‐dependent. Silencing of Sp4 blocked the up‐regulation of these genes induced by KCl, whereas over‐expression of Sp4 rescued them from TTX‐induced suppression. The effect of silencing or over‐expressing Sp4 on primary neurons was much greater than those of Sp1 or Sp3. The binding sites of Sp factors on these genes are conserved among mice, rats and humans. Thus, Sp4 plays an important role in the transcriptional coupling of energy generation and energy consumption in neurons.
Pathophysiology of epileptic encephalopathies
Authors: Lado Fred A. , Rubboli Guido , Capovilla Pippo , Avanzini Giuliano , Moshé Solomon L.
Published: November 2013

The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike‐wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.
Progress in a replicated selection for elevated blood ethanol concentrations in HDID mice
Authors: Crabbe J. C. , Metten P. , Belknap J. K. , Spence S. E. , Cameron A. J. , Schlumbohm J. P. , Huang L. C. , Barkley‐Levenson A. M. , Ford M. M. , Phillips T. J.
Published: November 2013

Drinking in the dark (DID) is a limited access ethanol‐drinking phenotype in mice. High Drinking in the Dark (HDID‐1) mice have been bred for 27 selected generations (S27) for elevated blood ethanol concentrations (BECs) after a 4‐h period of access to 20% ethanol. A second replicate line (HDID‐2) was started later from the same founder population and is currently in S20. An initial report of response to selection in HDID‐1 was published after S11. This article reports genetic and behavioral characteristics of both lines in comparison with the HS controls. Heritability is low in both replicates (h2 = 0.09) but the lines have shown 4–5 fold increases in BEC since S0; 80% of HDID‐1 and 60% of HDID‐2 mice reach BECs greater than 1.0 mg/ml. Several hours after a DID test, HDID mice show mild signs of withdrawal. Although not considered during selection, intake of ethanol (g/kg) during the DID test increased by approximately 80% in HDID‐1 and 60% in HDID‐2. Common genetic influences were more important than environmental influences in determining the similarity between BEC and intake for HDID mice. Analysis of the partitioning of intake showed that 60% of intake is concentrated in the last 2 h of the 4 h session. However, this has not changed during selection. Hourly BECs during the DID test reach peak levels after 3 or 4 h of drinking. HDID mice do not differ from HS mice in their rate of elimination of an acute dose of alcohol.
Brain morphology in children with 47,XYY syndrome: a voxel‐ and surface‐based morphometric study
Authors: Lepage J.‐F. , Hong D. S. , Raman M. , Marzelli M. , Roeltgen D. P. , Lai S. , Ross J. , Reiss A. L.
Published: November 2013

The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y‐chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y‐chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age‐matched healthy controls by combining voxel‐based morphometry (VBM) and surface‐based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y‐chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.
Vagrancy fails to predict colonization of oceanic islands
Authors: Lees Alexander C. , Gilroy James J.
Published: November 2013

Aim

Theories of island biogeography typically predict a close link between patterns of immigration and the dynamics of colonization and extinction on islands, but relatively little is known of the immigration process owing to the difficulty of observing immigration directly. We assess the relationship between propagule immigration and colonization success using records of out‐of‐range ‘vagrant’ animals compiled by amateur and professional biologists.

Location

A global sample of 66 oceanic islands and archipelagos.

Methods

We compiled a database of landbird records from each archipelago including occasional visitors (vagrants) and colonizers (defined as non‐endemic species with breeding populations on islands). Using a database of species traits for all the world's passerine and near‐passerine birds (migratory status and range size), we compared the characteristics of vagrants and colonizers and assessed how island characteristics influenced vagrant and colonizer communities.

Results

We show that variation in the propensity for vagrancy to oceanic islands world‐wide is a surprisingly poor predictor of colonization success across species on a global scale. Colonization success is positively related to global range size, and is higher for migrants than residents (particularly on higher‐latitude islands). Species richness of vagrant communities increases with the area and local isolation of island groups, and decreases with isolation from continents and latitude. Colonizer species richness increases with island area and decreases with isolation and latitude, and is little influenced by vagrant species richness.

Main conclusions

Contrary to expectations, we find that the capacity for trans‐oceanic dispersal may not be a key determinant of oceanic island colonization amongst landbirds.