bluuebunny/crossref_metadata_2025 huggingface dataset:
Caffeine counteracts impairments in task-oriented psychomotor performance induced by chlorpheniramine: a double-blind placebo-controlled crossover study
Authors: Kim Sung-Wan , Bae Kyung-Yeol , Shin Hee-Young , Kim Jae-Min , Shin Il-Seon , Kim Jong-Keun , Kang Gaeun , Yoon Jin-Sang
Published: June 2012

This study aimed to evaluate the effects of chlorpheniramine on psychomotor performance and the counteracting effects of caffeine on those sedative antihistamine actions. Sixteen healthy young men participated in this study. Using a double-blind placebo-controlled crossover design, each subject was administered one of the following conditions in a random order with a one-week interval: ‘placebo-placebo’, ‘4 mg of chlorpheniramine-placebo’, ‘placebo-200 mg of caffeine’ or ‘4 mg of chlorpheniramine-200 mg of caffeine’. Before and after the treatments, psychomotor functions were assessed using a battery of tests. Additionally, subjective responses were assessed using a visual analogue scale (VAS). Psychomotor performance changed over time in different ways according to the combination of study medications. In the ‘chlorpheniramine-placebo’ condition, reaction times of the compensatory tracking task were significantly impaired compared with the other three conditions. In addition, the number of omission errors of the continuous performance test were significantly greater compared with the ‘placebo-caffeine’ condition. However, the response pattern of the ‘chlorpheniramine-caffeine’ condition was not significantly different from that of the ‘placebo-placebo’ condition. Changes of VAS for sleepiness were significantly greater in the ‘chlorpheniramine-placebo’ condition compared with the other three conditions. In conclusion, chlorpheniramine significantly increases subjective sleepiness and objectively impairs psychomotor performance. However, caffeine counteracts these sedative effects and psychomotor impairments.
High velocity impact performance of three-dimensional woven composites
Authors: Udatha Pavani , Sesha Kumar Ch V , Nair Nithin S , Naik Niranjan K
Published: June 2012

Performance of three-dimensional orthogonal woven E-glass/epoxy composites under high velocity impact is presented. The analytical method used is based on wave propagation and energy balance between the projectile and the target. Different damage and energy absorbing mechanisms for a typical three-dimensional orthogonal woven composite are compression of the target directly below the projectile, compression in the surrounding region of the impacted zone, tension in the region consisting of primary yarns, tensile deformation in the region consisting of secondary yarns, shear plugging, bulge formation on the back face of the target, matrix cracking and friction between the target and the projectile. Experimental studies are also presented on high strain rate characterization, shear plugging behavior and high velocity impact behavior. For comparison, studies are also presented on the performance of two-dimensional plain weave E-glass/epoxy composites. A good match is observed between the analytical predictions and experimentally obtained limit velocities for complete penetration. It is observed that limit velocity for complete penetration for three-dimensional woven composite is higher than that for two-dimensional plain weave composite.
Pushing Family Reconstitution Further
Authors: Kennedy Gregory M. W.
Published: June 2012

This article proposes combining traditional family reconstitution methods using parish registers with the notary documents found in the Contrôle des Actes in early modern France. This approach enables the construction of detailed life histories that can combine and link demographic events with economic transactions and provide new insights into life course, socioeconomic hierarchy, and migration. While certain trends connected to life course events can be discerned, peasant experience was diverse and varied and heads of household actively invested, consolidated, or moved in response to their particular circumstances. These were practical decisions based on the multiple options available in their community and within the larger region.
In vitro evaluation of quaternized polydimethylaminoethylmethacrylate sub-microparticles for oral insulin delivery
Authors: Sonia TA , Sharma Chandra P
Published: June 2012

This investigation describes the synthesis and in vitro evaluation of cationic hydrogel sub-microparticles based on polydimethylaminoethylmethacrylate for oral insulin delivery. Polymerization of dimethylaminoethylmethacrylate was carried out in aqueous medium with potassium persulfate as the initiator. Quaternization of the resulting hydrogel was carried out to introduce cationic surface groups and the derivatization was confirmed by zeta potential measurements, nuclear magnetic resonance and infrared spectroscopies. Swelling behavior of these particles was evaluated for dependence of pH. Insulin-loaded particles were subjected to in vitro release experiments at gastric and intestinal pH. Moreover, cytotoxicity evaluation showed that both polydimethylaminoethylmethacrylate and its quaternized derivative were non-toxic to Caco-2 and L929 cell lines. The presence of quaternary ammonium groups improved the cationic charge and enhanced the mucoadhesive properties of the hydrogel. Confocal microscopic observations showed that these sub-microparticles were capable of opening tight junctions between the Caco-2 cells and thus increased the paracellular permeability. The above studies suggest that cationic hydrogel sub-microparticles can act as a good candidate for oral insulin delivery.
Novel polypyrrolones containing fluorenyl groups in the main chain: Synthesis and characterization
Authors: Li Hui , Zhang Shu-Jiang , Li Yan-Feng , Bu Qian-qian , Gong Chen-liang
Published: June 2012

A novel aromatic tetraamine, 2′,7′-bis(3,4-diaminophenoxy)-spiro(fluorene-9,9′- xanthene), was synthesized, which was employed to react with various commercial available aromatic dianhydrides to yield a series of polypyrrolones (PPys). The intermediate poly(amide amino acid) had inherent viscosities of 0.28–0.35 g/dl and could be thermally converted into lightly yellow PPys films. All the resulting PPys exhibited good thermal stabilities. The glass-transition temperatures were in the range of 371–386°C, and the temperatures of 5 and 10% weight loss were 472–549°C and 552–612°C in nitrogen, respectively; the residual weight was above 62% at 800°C. In addition, the PPys films had tensile strengths in the range of 42.3–85.8 MPa, tensile moduli of 1.8–2.5 GPa, and elongations at break of 6.8–7.4%. The polymer films also exhibited excellent alkaline hydrolysis resistance, retaining their original shapes and toughness after boiling for 7 days in 10% sodium hydroxide solution.
Preparation, thermal stability and flame-retardant properties of halogen-free polypropylene composites
Authors: Li Yi-Luen , Kuan Chen-Feng , Hsu Shu-Wei , Chen Chia-Hsun , Kuan Hsu-Chiang , Lee Fang-Mei , Yip Ming-Chuen , Chiang Chin-Lung
Published: June 2012

A flame retardant containing phosphorus and nitrogen was prepared. This halogen-free flame retardant was blended with polypropylene (PP) by hot melting to improve the flame-retardant capability and thermal stability of the composites. Fourier transform infrared spectroscopy, energy dispersive X-ray measurements, thermogravimetric analysis, limiting oxygen index (LOI) measurements, and UL-94 measurements were applied to characterize the structure and thermal and flame-retardant properties of the composites. When the flame-retardant concentration was 40 wt%, the LOI value of the composite was 40, passing the V-0 rating of the UL-94 test. The LOI and UL-94 data showed the composites have an excellent flame-retardant property. For a kinetic study of thermal degradation, Ozawa’s method was applied to calculate the activation energies of pure PP and the composites. Analytical results indicate that the composites had higher values, meaning they have better thermal stability.
Azo-polysiloxanes thermal stability study
Authors: Lisa Gabriela , Păiuş Cristina , Raicu-Luca Alina , Hurduc Nicolae
Published: June 2012

This paper presents a thermogravimetric study of azo-polysiloxanic materials that may be used as supports for cells culture. This type of polymer may generate nanostructured surfaces when subjected to laser irradiation, yielding a cell response that depends on surface relief. Modification of cell growth supports using nanostructured synthetic materials improves general understanding of the complex mechanisms that control cell adhesion and migration in normal conditions, as well as in various pathologies. These polymers require good thermal stability, since they need to be able to withstand both the interaction with the laser source, as well as various sterilization processes, without noticeable alteration in structure and properties. Thermal stability analysis confirms that the azo-polysiloxanic materials under study here may be used up to 300 °C in dynamic temperature conditions and also for a period of 40 minutes in isothermal conditions at 180 °C.
Impact source localization in plate utilizing multiple signal classification
Authors: Yang HongJun , Lee Young Jun , Lee Sang Kwon
Published: June 2012

This article proposed a multiple signal classification method based on array signal processing for impact source localization in a plate. For source localization, the direction of arrival of the wave caused by an impact on a plate and the distance between the impact position and sensor should be estimated. The direction of arrival can be estimated accurately using the multiple signal classification method; the distance can be obtained using the time delay of arrival and the group velocity of the Lamb wave in a plate. The time delay of arrival is experimentally estimated using the continuous wavelet transform for the wave. The group velocity is theoretically obtained based on the elastodynamic theory.
Methods for meta-analysis of individual participant data from Mendelian randomisation studies with binary outcomes
Authors: Burgess Stephen , Thompson Simon G ,   CRP CHD Genetics Collaboration
Published: June 2012

Mendelian randomisation is an epidemiological method for estimating causal associations from observational data by using genetic variants as instrumental variables. Typically the genetic variants explain only a small proportion of the variation in the risk factor of interest, and so large sample sizes are required, necessitating data from multiple sources. Meta-analysis based on individual patient data requires synthesis of studies which differ in many aspects. A proposed Bayesian framework is able to estimate a causal effect from each study, and combine these using a hierarchical model. The method is illustrated for data on C-reactive protein and coronary heart disease (CHD) from the C-reactive protein CHD Genetics Collaboration (CCGC). Studies from the CCGC differ in terms of the genetic variants measured, the study design (prospective or retrospective, population-based or case-control), whether C-reactive protein was measured, the time of C-reactive protein measurement (pre- or post-disease), and whether full or tabular data were shared. We show how these data can be combined in an efficient way to give a single estimate of causal association based on the totality of the data available. Compared to a two-stage analysis, the Bayesian method is able to incorporate data on 23% additional participants and 51% more events, leading to a 23–26% gain in efficiency.
The Irish bifocal and American sport: Exploring racial formation in the Irish Diaspora
Authors: Dunne Sean
Published: June 2012

Departing from previous research that focused only on how ‘the Irish’ became White, this essay will instead explore how the color line was used to define and divide the Irish Diaspora in the United States. The color line will be used as part of a bifocal perspective on the Irish Diaspora, which examines how certain sections of the Irish Diaspora became White and how others became Black. This approach can provide critical insights into the workings of racial formations by highlighting the social and political nature of race and tracing the concept’s historical flexibility. A historical overview of the interactions between Irish American athletes and American sport is conducted to reveal many racial variations and tensions found within the Irish Diaspora. While sport has actively contributed to these Irish racial formations, it can also be used to challenge and transform the foundations of the racial formations that are currently found in American society.
Green Olympics, green legacies? An exploration of the environmental legacies of the Olympic Games
Authors: Samuel Shalini , Stubbs Wendy
Published: June 2012

The ‘greening’ of mega-sporting events such as the Olympic Games (OG) has become an increasing priority of event organizers in the past two decades. This paper explores the legacies from the greening of the OG through an analysis of Beijing 2008, Singapore 2010, and London 2012, drawing on interviews with key stakeholders. While each OG is different, the key determinants for green legacies include: the breadth and depth of environmental commitments during the bid process; embedding sustainability in the vision, mission and branding of organizing committees; embedding sustainability in various aspects of OG organization, which is an important practical application of a sustainability vision; and the transfer of knowledge from one OG to the next, allowing newer host cities to enhance green legacies. The findings indicate institutionalization of elements of sustainability in the OG with legitimation and mimetic processes at play. The study found that legitimation is a key strategy during the bidding process and in operations of the OG.
‘Reflexive modernity’ and the transition experiences of university athletes
Authors: Falls Dominique , Wilson Brian
Published: June 2012

Although there is a tradition of research focused on the socialization experiences of student-athletes, few studies consider how non-sport-related transitions impact and overlap with the sport-related transitions experienced by these athletes – or how transition experiences are influenced by the broader, structural conditions associated with reflexive modernity. With the goal of addressing these gaps, an interview-based study of the experiences of 12 female student-athletes, who moved from Canada to the United States to pursue intercollegiate soccer, is reported. The study is situated in literatures related to youth transitions, mobility, sport-related socialization, and identity formation. The ‘individualization’ and ‘detraditionalization’ concepts are featured and considered for their pertinence to the experiences of the interviewed student-athletes. Key findings from the study include the following: decision-making by student-athletes was a predominantly individualized endeavor that was influenced by various sport and non-sport-related factors; the sport and non-sport-related transitions that accompanied the move to a new sporting and educational context were eased because of the (temporary and conditional) support of teammates; and that the transition out of sport was especially difficult for many of the athletes, as the support structures associated with ‘the team’ quickly diminished – and because of the hyper-individualized identities that the student-athletes were required to renegotiate.
The Form and Function of “Bullying” Behaviors in a Strong Occupational Culture
Authors: Miller Hilary , Rayner Charlotte
Published: June 2012

The study examines the persistence of bullying in a high-teamwork environment using self-categorization theory (SCT) and interaction ritual chain theory (IRCT). Findings from a qualitative study suggest that “isolation” is the key behavior police officers label as bullying and that other behaviors thought of as bullying may be tolerated, providing there is no exclusion. IRCT clarified the dynamics, whereas SCT explained the motivation for engaging in rituals containing behaviors that included bullying. The study posits a new framework for bullying in high-pressured teams and accounts for the tolerance to “bullying” behaviors in such work environments. Implications for addressing workplace bullying in these contexts are discussed.
Analyzing the effect of landmark vectors in homing navigation
Authors: Yu Seung-Eun , Lee Changmin , Kim DaeEun
Published: June 2012

The development of an autonomous navigating robot is a challenging task. Motivated by the performance of insects successfully returning to the nest, researchers have studied bio-inspired navigation algorithms for their potential use in mobile robots. In this paper, we analyze landmark-based approaches, especially Distance Estimated Landmark Vector (DELV), Average Correctional Vector and Average Landmark Vector methods, that use landmark vectors for visible environmental landmarks. We evaluated the homing performance of various landmark vector methods with surrounding landmarks under occlusion and found that the occluded or missing landmarks have a significant influence on the performance. We also developed a landmark vector algorithm with a visual compass that uses only retinal images without a reference compass. From our experimental results, we conclude that the DELV shows robust homing navigation performance with missing or occluded landmarks among landmark vector methods.
Career Thoughts, Indecision, and Depression
Authors: Walker Jerry V. , Peterson Gary W.
Published: June 2012

This study investigated the relationships among dysfunctional career thoughts and career indecision with respect to symptoms of depression. Such information could be useful to counselors in identifying individuals at the outset of career counseling who may be experiencing emotional distress from life stressors in addition to career stress. One-hundred fifty-eight college students enrolled in a career development course completed measures of dysfunctional career thoughts, an occupational alternative question, and a measure of depression symptoms. Results indicated that dysfunctional career thoughts and occupational indecision were related to depression symptoms, with decision-making confusion being the best predictor. Implications of the findings for practice and research are discussed.
Ecological Modernization in Evolutionary Perspective
Authors: McLaughlin Paul
Published: June 2012

Ecological modernization theory (EMT) has emerged as a major theoretical and policy-making perspective. Despite its growing influence, EMT has significant limitations both as a descriptive and as a prescriptive theory. Taking the Darwinian revolution’s rejection of essentialism and developmentalism as the touchstone for ecological thinking, the author argues that EMT is premised on a nonecological foundation. The nonecological underpinnings of EMT preclude its elaboration into a descriptive theory capable of conceptualizing the interactions between social structures, human agency, and biophysical environments. As a prescriptive theory, these same assumptions marginalize people and projects that depart from EMT’s restricted vision of modernization. The author concludes by contrasting EMT with an evolutionary perspective on social change, premised on the concept of a socially constructed adaptive landscape, which combines population thinking with moderate constructionist insights into agency and culture. From the latter perspective, EMT’s prescriptive claims can be interpreted as a form of strategic essentialism.
Chondroma of the vertical ramus of the feline mandible
Authors: Hodik Vyacheslav , Loeb Emmanuel , Ranen Eyal
Published: June 2012

A 5-year-old, castrated male, domestic shorthair cat presented with firm swelling in the right temporal region of the skull. The cat’s jaws were almost locked in the closed position. Radiographs showed a mass with an irregular mineralized matrix superimposed on the caudal right mandible and temporomandibular joint. Surgical exploration revealed that the mass arose from the proximal part of the vertical ramus, which was removed, with the exclusion of the temporomandibular joint. It was possible to open the cat’s mouth to nearly normal extension immediately after surgery. Recovery was uneventful — the cat has had no problem eating and no mass recurrence has been detected 3 years after surgery. Histological examination of the mass was consistent with chondroma. To the best of our knowledge, this is the first clinical and pathological description of a chondroma in cats, and one of the rare cases describing clinical presentation and management of primary bone tumours involving the vertical ramus of the feline mandible.
Thoracoscopic en bloc thoracic duct sealing and partial pericardectomy for the treatment of chylothorax in two cats
Authors: Haimel Georg , Liehmann Lea , Dupré Gilles
Published: June 2012

Two cats with intractable idiopathic chylothorax and a history of unsuccessful medical management were treated thoracoscopically with en bloc thoracic duct sealing and subtotal pericardectomy using a bipolar feedback-controlled vessel sealing device. No surgical complications were observed. Twenty-four and 26 months after surgery, both cats were free of thoracic effusion and clinical signs.
Reflexive practice and the making of elite business careers
Authors: Maclean Mairi , Harvey Charles , Chia Robert
Published: June 2012

This article develops a new perspective on reflexive practice in the making of elite business careers. It builds upon Bourdieu’s practice framework to examine how business leaders from elite and non-elite backgrounds develop and practice reflexivity in their everyday lives. The article draws upon in-depth life-history interviews with members of the British business elite. Elites exhibited five types of reflexive behaviour, from which two modes of reflexive practice were derived: an accumulative mode, through which business leaders reflexively accumulate capital, positions and perspectives; and a re-constructive mode, through which they re-constitute the self in response to contingences, contexts and insights gathered. Our analysis suggests a link between reflexivity and career advancement, particularly in the case of non-privileged elites. Their greater experience of navigating the social landscape may facilitate perspective-taking, enhancing multipositionality, enabling such individuals to seize opportunities previously unthinkable.
The combination of OLmesartan and a CAlcium channel blocker (azelnidipine) or candesartan and a calcium channel blocker (amlodipine) in type 2 diabetic hypertensive patients: The OLCA study
Authors: Daikuhara Hiroyuki , Kikuchi Fumi , Ishida Toshihiko
Published: June 2012

Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.
Albumin-Coated Bioactive Suture for Cell Transplantation
Authors: Horváthy Dénes Balázs , Vácz Gabriella , Cselenyák Attila , Weszl Miklós , Kiss Levente , Lacza Zsombor
Published: June 2012

Cell therapy holds the promise for a novel modality in the surgical toolkit; however, delivery of cells into damaged soft tissues constitutes a challenge. The authors hypothesized that growing stem cells on the surface of absorbable sutures in vitro and then implanting them via stitching would be a suitable delivery route for cell therapy. Fibronectin, poly-L-lysine, and albumin coatings were used to increase attachment of human and rat bone-marrow-derived mesenchymal stem cells (BMSC) to polyfilament absorbable sutures in vitro. Fluorescence microscopy was performed to localize the cells on the suture. After 48 hours of incubation, the albumin-coated sutures had the highest cell number, and after 168 hours cell number reached confluency. In the in vivo experiments, a 10-mm incision was made on the triceps surae muscle of male Wistar rats and rat BMSC coated sutures were placed into the muscle. Two days after the implantation, cells were seen on the surface of the sutures as well as in the surrounding muscle tissue. Long-term results at 5 weeks showed that transplanted cells survived and the sutures were partly absorbed. In conclusion, coating absorbable sutures with proteins, especially serum albumin, improves attachment and proliferation of cells, and only 48 hours in culture is enough to cover the sutures sufficiently. Using these stitches in vivo resulted in short-term and long-term survival of cells. As a result, albumin-coated suture can be a vehicle for stem cell therapy in soft tissues such as muscle, tendon, or peripheral nerves.
Flexible Single-Incision Surgery
Authors: Noguera José F. , Dolz Carlos , Cuadrado Angel , Olea José , García Juan
Published: June 2012

Introduction. The development of natural orifice transluminal endoscopic surgery has led to other techniques, such as single-incision surgery. The use of the flexible endoscope for single-incision surgery paves the way for further refinement of both surgical methods. Objective. To describe a new, single-incision surgical technique, namely, flexible single-incision surgery. Patients and Methods. Assessment of the safety and effectiveness of endoscopic cholecystectomy in a series of 30 patients. This technique consists of a single umbilical incision through which a flexible endoscope is introduced and consists of 2 parallel entry ports that provide access to nonarticulated laparoscopic instruments. Results. The technique was applied in all patients for whom it was prescribed. No general or surgical wound complications were noted. Surgical time was no longer than usual for single-port surgery. Conclusions. Flexible single-incision surgery is a new single-site surgical technique offering the same level of patient safety, with additional advantages for the surgeon at minimal cost.
Missing Funds
Authors: Hassenpflug Ann
Published: June 2012

A high school drama coach informs assistant principal Laura Madison that the money students earned through fund-raising activities seems to have vanished and that the male assistant principal may be involved in the disappearance of the funds. Laura has to determine how to address this situation. She considers her past experiences with problematic practices related to school funds. She tries to figure out how to handle this unwanted problem in an ethical manner that will allow her to demonstrate professional responsibility without harming her career. This case can be used in a course on management of physical resources or on organizational leadership.
In living memory: Mapping the landscape of Greenham and Crookham Commons
Authors: Jardine Brown Catriona H
Published: June 2012

Greenham and Crookham Commons in West Berkshire, UK, are geographic places identifiable on satellite images and survey maps. This article complicates simple physical mappings of the Commons by analysing the mental maps that emerge from the recorded memories of 12 elderly participants engaged in a ‘reminiscence project’. Originally part of a community sound installation, the recordings provide insights into lives lived in and around the Commons from the early 20th century to the present day. Following a chronological structure linked to the geographical features of the Commons, the article examines myths and stories associated with these shared spaces as they were transformed by time, history and ageing. Early childhood memories of the landscape of the Commons create a virtual cartography that brings to the fore experiences of daily life and practices of space belonging to earlier generations. These memories are set in stark contrast to the memories of the US army occupation of the Commons, and of the anti-nuclear protests that made them famous. Considering these virtual cartographies enables reflections on the relationship between memory, space and landscape over time as well as on the unique ways in which old age may alter conceptions of space in shared reminiscences.
CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte
Authors: Delarue Richard , Haioun Corinne , Ribrag Vincent , Brice Pauline , Delmer Alain , Tilly Herve , Salles Gilles , Van Hoof Achiel , Casasnovas Olivier , Brousse Nicole , Lefrere Francois , Hermine Olivier
Published: June 2012

Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP21 with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP21 induction in a multicentric European protocol.
CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis
Authors: Jiang Tianxia , Zhuang Jie , Duan Hongxia , Luo Yongting , Zeng Qiqun , Fan Kelong , Yan Huiwen , Lu Di , Ye Zhongde , Hao Junfeng , Feng Jing , Yang Dongling , Yan Xiyun
Published: June 2012

CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146EC-KO). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis.
The B subunits of Shiga-like toxins induce regulated VWF secretion in a phospholipase D1–dependent manner
Authors: Huang Jing , Haberichter Sandra L. , Sadler J. Evan
Published: June 2012

Shiga toxin (Stx) causes diarrhea-associated hemolytic uremic syndrome by damaging renal microvascular endothelium. The pentameric B subunits of Stx types 1 and 2 (Stx1B and Stx2B) are sufficient to stimulate acute VWF secretion from endothelial cells, but Stx1B and Stx2B exert distinct effects on Ca2+ and cAMP pathways. Therefore, we investigated other signaling components in StxB-induced VWF exocytosis. Incubation of HUVECs with StxB transiently increased phospholipase D (PLD) activity. Inhibition of PLD activity or shRNA-mediated PLD1 knockdown abolished StxB-induced VWF secretion. In addition, treatment with StxB triggered actin polymerization, enhanced endothelial monolayer permeability, and activated RhoA. PLD activation and VWF secretion induced by Stx1B were abolished on protein kinase Cα (PKCα) inhibition or gene silencing but were only moderately reduced by Rho or Rho kinase inhibitors. Conversely, PLD activation and VWF exocytosis induced by Stx2B were reduced by Rho/Rho kinase inhibitors and dominant-negative RhoA, whereas attenuation of PKCα did not affect either process. Another PLD1 activator, ADP-ribosylation factor 6, was involved in VWF secretion induced by Stx1B or Stx2B, but not histamine. These data indicate that Stx1B and Stx2B induce acute VWF secretion in a PLD1-dependent manner but do so by differentially modulating PKCα, RhoA, and ADP-ribosylation factor 6.
A novel splice variant of folate receptor 4 predominantly expressed in regulatory T cells
Authors: Tian Yi , Wu Guoqiang , Xing Jun-Chao , Tang Jun , Zhang Yi , Huang Ze-Min , Jia Zheng-Cai , Zhao Ren , Tian Zhi-Qiang , Wang Shu-Feng , Chen Xiao-Ling , Wang Li , Wu Yu-Zhang , Ni Bing
Published: June 2012

Background

Regulatory T cells (Tregs) are required for proper maintenance of immunological self-tolerance and immune homeostasis. Folate receptor 4 (FR4) is expressed at high levels in transforming growth factor-beta (TGF-β)-induced Tregs and natural Tregs. Moreover, antibody-mediated targeting of FR4 is sufficient to mediate Treg depletion.

Results

In this study, we describe a novel FR4 transcript variant, FR4D3, in which exon 3 is deleted. The mRNA of FR4D3 encodes a FR4 variant truncated by 189 bp. FR4D3 was found to be predominantly expressed in CD4+CD25+ Treg cells. Overexpression of FR4D3 in CD4+CD25+ Treg cells in vitro stimulated proliferation, which may modulate the ability of these cells to bind and incorporate folic acid.

Conclusions

Our results suggested that high levels of FR4D3 may be critical to support the substantial proliferative capacity of Treg cells.
Aspergillus flavus grown in peptone as the carbon source exhibits spore density- and peptone concentration-dependent aflatoxin biosynthesis
Authors: Yan Shijuan , Liang Yating , Zhang Jindan , Liu Chun-Ming
Published: June 2012

Background

Aflatoxins (AFs) are highly carcinogenic compounds produced by Aspergillus species in seeds with high lipid and protein contents. It has been known for over 30 years that peptone is not conducive for AF productions, although reasons for this remain unknown.

Results

In this study, we showed that when Aspergillus flavus was grown in peptone-containing media, higher initial spore densities inhibited AF biosynthesis, but promoted mycelial growth; while in glucose-containing media, more AFs were produced when initial spore densities were increased. This phenomenon was also observed in other AF-producing strains including A. parasiticus and A. nomius. Higher peptone concentrations led to inhibited AF production, even in culture with a low spore density. High peptone concentrations did however promote mycelial growth. Spent medium experiments showed that the inhibited AF production in peptone media was regulated in a cell-autonomous manner. mRNA expression analyses showed that both regulatory and AF biosynthesis genes were repressed in mycelia cultured with high initial spore densities. Metabolomic studies revealed that, in addition to inhibited AF biosynthesis, mycelia grown in peptone media with a high initial spore density showed suppressed fatty acid biosynthesis, reduced tricarboxylic acid (TCA) cycle intermediates, and increased pentose phosphate pathway products. Additions of TCA cycle intermediates had no effect on AF biosynthesis, suggesting the inhibited AF biosynthesis was not caused by depleted TCA cycle intermediates.

Conclusions

We here demonstrate that Aspergillus species grown in media with peptone as the sole carbon source are able to sense their own population densities and peptone concentrations to switch between rapid growth and AF production. This switching ability may offer Aspergillus species a competition advantage in natural ecosystems, producing AFs only when self-population is low and food is scarce.
The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation
Authors: Nagler Arnon , Cytron Samuel , Mashevich Maya , Korenstein-Ilan Avital , Avivi Lydia
Published: June 2012

Background

Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT).

Methods

TP53 (a tumor suppressor gene assigned to chromosome 17), AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation) and the pericentomeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH) technology applied to phytohemagglutinin (PHA)-stimulated lymphocytes.

Results

We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations) displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state). A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged.

Conclusions

The reversible nature of the replication aberrations may serve as potential epigenetic blood markers for evaluating the success of transplant or other treatments and for long-term follow up of the patients who have overcome a hematological malignancy.
Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome
Authors: Xu Jia , Shetty Priya B , Feng Weiwei , Chenault Carol , Bast Robert C , Issa Jean-Pierre J , Hilsenbeck Susan G , Yu Yinhua
Published: June 2012

Background

Aberrant promoter CpG island hypermethylation is associated with transcriptional silencing. Tumor suppressor genes are the key targets of hypermethylation in breast cancer and therefore may lead to malignancy by deregulation of cell growth and division. Our previous pilot study with pairs of malignant and normal breast tissues identified correlated methylation of two pairs of genes - HIN-1/RASSFIA and RIL/CDH13 - with expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 (HER2). To determine the impact of methylation on clinical outcome, we have conducted a larger study with breast cancers for which time to first recurrence and overall survival are known.

Methods

Tumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival.

Results

In this study, we found that ER was associated with RASSF1A methylation (p < 0.001) and HIN-1 methylation (p = 0.002). PR was associated with RIL methylation (p = 0.012), HIN-1 (p = 0.002), and RASSF1A methylation (p = 0.019). Tumor size was associated with RIL and CDH13 methylation (both p = 0.002), and S-phase was associated with RIL methylation (p = 0.036). Only RASSF1A was associated with worse time to first recurrence (p = 0.045) and worse overall survival (p = 0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor.

Conclusions

Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.
Methylation signature of lymph node metastases in breast cancer patients
Authors: Barekati Zeinab , Radpour Ramin , Lu Qing , Bitzer Johannes , Zheng Hong , Toniolo Paolo , Lenner Per , Zhong Xiao Yan
Published: June 2012

Background

Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.

Methods

The quantitative methylation analysis was performed using the SEQUENOM’s EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).

Results

The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.

Conclusions

The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.
Pirfenidone inhibits TGF-β1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells
Authors: Hisatomi Keiko , Mukae Hiroshi , Sakamoto Noriho , Ishimatsu Yuji , Kakugawa Tomoyuki , Hara Shintaro , Fujita Hanako , Nakamichi Seiko , Oku Hisashi , Urata Yoshishige , Kubota Hiroshi , Nagata Kazuhiro , Kohno Shigeru
Published: June 2012

Background

Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF). We previously showed that pirfenidone inhibits the over-expression of collagen type I and of heat shock protein (HSP) 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor (TGF)-β1 in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary fibrosis induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro.

Methods

The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with TGF-β1 was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining.

Results

TGF-β1 stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by TGF-β1.

Conclusion

We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung fibrosis. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.
Improved adhesive properties of recombinant bifidobacteria expressing the Bifidobacterium bifidum-specific lipoprotein BopA
Authors: Gleinser Marita , Grimm Verena , Zhurina Daria , Yuan Jing , Riedel Christian U
Published: June 2012

Background

Bifidobacteria belong to one of the predominant bacterial groups in the intestinal microbiota of infants and adults. Several beneficial effects on the health status of their human hosts have been demonstrated making bifidobacteria interesting candidates for probiotic applications. Adhesion of probiotics to the intestinal epithelium is discussed as a prerequisite for colonisation of and persistence in the gastrointestinal tract.

Results

In the present study, 15 different strains of bifidobacteria were tested for adhesion. B. bifidum was identified as the species showing highest adhesion to all tested intestinal epithelial cell (IEC) lines. Adhesion of B. bifidum S17 to IECs was strongly reduced after treatment of bacteria with pronase. These results strongly indicate that a proteinaceous cell surface component mediates adhesion of B. bifidum S17 to IECs. In silico analysis of the currently accessible Bifidobacterium genomes identified bopA encoding a lipoprotein as a B. bifidum-specific gene previously shown to function as an adhesin of B. bifidum MIMBb75. The in silico results were confirmed by Southern Blot analysis. Furthermore, Northern Blot analysis demonstrated that bopA is expressed in all B. bifidum strains tested under conditions used to cultivate bacteria for adhesion assays. The BopA gene was successfully expressed in E. coli and purified by Ni-NTA affinity chromatography as a C-terminal His6-fusion. Purified BopA had an inhibitory effect on adhesion of B. bifidum S17 to IECs. Moreover, bopA was successfully expressed in B. bifidum S17 and B. longum/infantis E18. Strains overexpressing bopA showed enhanced adhesion to IECs, clearly demonstrating a role of BopA in adhesion of B. bifidum strains.

Conclusions

BopA was identified as a B. bifidum-specific protein involved in adhesion to IECs. Bifidobacterium strains expressing bopA show enhanced adhesion. Our results represent the first report on recombinant bifidobacteria with improved adhesive properties.