bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclin D3 Compensates for the Loss of Cyclin D1 during ErbB2-Induced Mammary Tumor Initiation and Progression
Authors: Zhang Qian , Sakamoto Kazuhito , Liu Chengbao , Triplett Aleata A. , Lin Wan-chi , Rui Hallgeir , Wagner Kay-Uwe
Published: October 2011

Cyclin D1 regulates cell proliferation and is a candidate molecular target for breast cancer therapy. This study addresses whether Cyclin D1 is indispensable for ErbB2-associated mammary tumor initiation and progression using a breast cancer model in which this cell-cycle regulator can be genetically ablated prior to or after neoplastic transformation. Deficiency in Cyclin D1 delayed tumor onset but did not prevent the occurrence of mammary cancer in mice overexpressing wild-type ErbB2. The lack of Cyclin D1 was associated with a compensatory upregulation of Cyclin D3, which explains why the targeted downregulation of Cyclin D1 in established mammary tumors had no effect on cancer cell proliferation. Cyclin D1 and D3 are overexpressed in human breast cancer cell lines and primary invasive breast cancers, and Cyclin D3 frequently exceeded the expression of Cyclin D1 in ErbB2-positive cases. The simultaneous inhibition of both cyclins in mammary tumor cells reduced cancer cell proliferation in vitro and decreased the tumor burden in vivo. Collectively, the results of this study suggest that only the combined inhibition of Cyclin D1 and D3 might be a suitable strategy for breast cancer prevention and therapy. Cancer Res; 71(24); 7513–24. ©2011 AACR.
Targeted Therapy for BRAFV600E Malignant Astrocytoma
Authors: Nicolaides Theodore P. , Li Huifang , Solomon David A. , Hariono Sujatmi , Hashizume Rintaro , Barkovich Krister , Baker Suzanne J. , Paugh Barbara S. , Jones Chris , Forshew Tim , Hindley Guy F. , Hodgson J. Graeme , Kim Jung-Sik , Rowitch David H. , Weiss William A. , Waldman Todd A. , James C. David
Published: October 2011

Purpose: Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAFV600E) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAFV600E in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAFV600E and wild-type BRAF MA.

Experimental Design: BRAFV600E mutation status was examined in two pediatric MA patient cohorts. For functional studies, BRAFV600E MA cell lines were used to investigate the effects of BRAF shRNA knockdown in vitro, and to investigate BRAF pharmacologic inhibition in vitro and in vivo.

Results: BRAFV600E mutations were identified in 11 and 10% of MAs from two distinct series of tumors (six of 58 cases total). BRAF was expressed in all MA cell lines examined, among which BRAFV600E was identified in four instances. Using the BRAFV600E-specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential antiproliferative activity against BRAFV600E mutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAF mutation status. Using orthotopic MA xenografts, we show that PLX4720 treatment decreases tumor growth and increases overall survival in mice-bearing BRAFV600E mutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF.

Conclusions: Our results indicate a 10% incidence of activating BRAFV600E among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAFV600E-specific inhibitors for treating BRAFV600E MA patients. Clin Cancer Res; 17(24); 7595–604. ©2011 AACR.
Pharmacodynamic Study Using FLT PET/CT in Patients with Renal Cell Cancer and Other Solid Malignancies Treated with Sunitinib Malate
Authors: Liu Glenn , Jeraj Robert , Vanderhoek Matt , Perlman Scott , Kolesar Jill , Harrison Michael , Simoncic Urban , Eickhoff Jens , Carmichael Lakeesha , Chao Bo , Marnocha Rebecca , Ivy Percy , Wilding George
Published: October 2011

Purpose: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3′-deoxy-3′-[18F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging.

Patients and Methods: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points.

Results: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUVmean) increased +15% (range: −14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: −5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal.

Conclusions: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early “angiogenic escape.” Clin Cancer Res; 17(24); 7634–44. ©2011 AACR.
Epratuzumab–SN-38: A New Antibody–Drug Conjugate for the Therapy of Hematologic Malignancies
Authors: Sharkey Robert M. , Govindan Serengulam V. , Cardillo Thomas M. , Goldenberg David M.
Published: October 2011

We previously found that slowly internalizing antibodies conjugated with SN-38 could be used successfully when prepared with a linker that allows approximately 50% of the IgG-bound SN-38 to dissociate in serum every 24 hours. In this study, the efficacy of SN-38 conjugates prepared with epratuzumab (rapidly internalizing) and veltuzumab (slowly internalizing), humanized anti-CD22 and anti-CD20 IgG, respectively, was examined for the treatment of B-cell malignancies. Both antibody–drug conjugates had similar nanomolar activity against a variety of human lymphoma/leukemia cell lines, but slow release of SN-38 compromised potency discrimination in vitro even against an irrelevant conjugate. When SN-38 was stably linked to the anti-CD22 conjugate, its potency was reduced 40- to 55-fold. Therefore, further studies were conducted only with the less stable, slowly dissociating linker. In vivo, similar antitumor activity was found between CD22 and CD20 antibody–drug conjugate in mice-bearing Ramos xenografts, even though Ramos expressed 15-fold more CD20 than CD22, suggesting that the internalization of the epratuzumab–SN-38 conjugate (Emab–SN-38) enhanced its activity. Emab–SN-38 was more efficacious than a nonbinding, irrelevant IgG–SN-38 conjugate in vivo, eliminating a majority of well-established Ramos xenografts at nontoxic doses. In vitro and in vivo studies showed that Emab–SN-38 could be combined with unconjugated veltuzumab for a more effective treatment. Thus, Emab–SN-38 is active in lymphoma and leukemia at doses well below toxic levels and therefore represents a new promising agent with therapeutic potential alone or combined with anti-CD20 antibody therapy. Mol Cancer Ther; 11(1); 224–34. ©2011 AACR.
Distribution of Inflammation Within Carotid Atherosclerotic Plaques With High-Risk Morphological Features
Authors: Figueroa Amparo L. , Subramanian Sharath S. , Cury Ricardo C. , Truong Quynh A. , Gardecki Joseph A. , Tearney Guillermo J. , Hoffmann Udo , Brady Thomas J. , Tawakol Ahmed
Published: October 2011

Background—

Several high-risk morphological features (HRM) of plaques, especially in combination, are associated with an increased risk of a clinical event. Although plaque inflammation is also associated with atherothrombosis, the relationship between inflammation and number of HRM is not well understood.

Methods and Results—

Thirty-four patients underwent
18
flurodeoxyglucose positron emission tomography (FDG-PET) imaging, and carotid atherosclerotic inflammation was assessed (target-to-background ratio). Additionally, in a subset of 10 subjects with carotid stenosis who underwent carotid endarterectomy, inflammation was histologically assessed (CD68 staining). Vessel wall morphology was examined using computed tomography for the presence of visible plaque and presence of 3 HRM: positive remodeling, luminal irregularity, and low attenuation. A total of 100 vascular segments were analyzed, of which 69 contained visible plaque (26 plaques with ≥1 HRM). Inflammation, by FDG uptake (target-to-background ratio), was higher in plaques with (versus without) HRM (mean±SEM: 2.21±0.20 versus 1.66±0.07,
P
=0.0003) and increased with the number of HRM observed (
P
<0.001 for trend). Similarly, inflammation within atherosclerotic specimens (% CD68 staining) was higher in plaques with (versus without) HRM (median [interquartile range]: 10 [0, 19.85] versus 0 [0, 1.55],
P
=0.01) and increased with the number of HRM observed (
P
<0.001 for trend).

Conclusions—

Inflammation, as assessed by both FDG uptake and histology, is increased in plaques containing HRM and increases with increasing number of HRM. These data support the concept that inflammation accumulates relative to the burden of morphological abnormalities.
Zerahia Halevi Saladin and Thomas Aquinas on Vows
Authors: Ackerman Ari
Published: October 2011

This article examines two medieval sermons that examine philosophic and halakhic issues: the Passover sermon of Hasdai Crescas, which discusses the laws of Passover, and a sermon of Zerahia Halevi Saladin, a disciple of Crescas, which probes an aspect of the laws of vows (nedarim). In the analysis of Zerahia’s sermon, a comparison is made between his discussion and Thomas Aquinas’s examination of vows in his Summa Theologica. The comparison establishes the dependency of Zerahia on Aquinas regarding this issue. Likewise, Zerahia’s sermon is compared with Crescas’s, and the relationship between the legal theories of Crescas and Zerahia is investigated. The articles concludes with a brief examination of the significance of the analysis these sermons for understanding of the impact of scholastic sources on Spanish-Jewish philosophy and the relationship between law and philosophy in the writings of Hasdai Crescas and his students.
Being and the Good: Maimonides on Ontological Beauty
Authors: Lobel Diana
Published: October 2011

Maimonides expresses the view that being is goodness; evil is a deprivation of being and goodness. This view is prominent in Neoplatonism but has strong roots in Aristotle as well.

While Maimonides problematizes moral language of good and evil, he makes use of an ontological sense of Necessary Existence as the absolute good. Plotinus wrote that beings are the beautiful. Avicenna adds that the pure good is Necessary Existence, which is free of deficiency, as it has no possibility of lacking existence. This notion has a strong Aristotelian core. Despite his strictures on language about the divine, Maimonides allows himself to express this vision—an affective-aesthetic appreciation as well as a purely cognitive one. Being is the absolute good, the source of ontological beauty and value.
Oil for Rome During the Second and Third Century AD: A Confrontation of Archaeological Records and the Historia Augusta
Authors: Broekaert Wim
Published: October 2011

It is well known that, according to the Historia Augusta, Septimius Severus introduced regular and official oil distributions in Rome. It is argued that this decision should not be interpreted to be a major change in economic policies, but merely an administrative reform to ease the shipment of oil amphorae. The archaeological evidence, inscriptions and legal texts clearly indicate that the imports peaked during the reign of the Antonines, suggesting that Severus neither started nor intensified the imports, but levelled out the structural differences between grain and oil traffic.
Context-sensitive Argumentation: Dirty Tricks in the Sophistical Refutations and a Perceptive Medieval Interpretation of the Text
Authors: Ebbesen Sten
Published: October 2011

Aristotle in the central chapters of his Sophistical Refutations gives advice on how to counter unfair argumentation by similar means, all the while taking account not only of the adversary’s arguments in themselves, but also of his philosophical commitments and state of mind, as well as the impression produced on the audience. This has offended commentators, and made most of them, medieval and modern alike, pass lightly over the relevant passages. A commentary that received the last touch in the very early 13th century is more perceptive because, it is argued, the commentator had lived in a 12th-century environment of competing Parisian schools that was in important respects similar to the one of Aristotle’s Athens.
Henry of Ghent on Teaching Theology
Authors: Spruyt Joke
Published: October 2011

This paper aims to explain Henry of Ghent’s views on what kind of language is appropriate in theology, and why. It concentrates on a number of questions of the Summa quaestionum ordinariarum, which are devoted to his take on how theologians should explain their discipline to students, and to the meaningfulness in general of theological language. The paper delves into the technical terms sensus and insinuare, and compares Henry’s account with H.P. Grice’s views on (speaker-)meaning and his notion of ‘conversational implicatures’, thus showing that Henry emphasises the performative features of linguistic use.
Medieval Obligationes as a Theory of Discursive Commitment Management
Authors: Novaes Catarina Dutilh
Published: October 2011

In earlier work, I have presented an interpretation of Obligationes as logical games of consistency maintenance; this interpretation has some advantages, in particular that of capturing the multi-agent, goal-oriented, rule-governed nature of the enterprise by means of the game analogy. But it has as its main limitation the fact that it does not provide a satisfactory account of the deontic aspect of the framework—i.e. of what being obliged to a certain statement consists in. In order to remedy this shortcoming, this paper argues for the more encompassing thesis that Obligationes can be viewed as a theory of rational dialogical practices, in particular concerning the management of one’s discursive commitments. The main inspiration for this interpretation comes from R. Brandom’s inferentialist, normative pragmatism, but more generally, it relies heavily on a dialogical conception of logic. I argue that it offers a more compelling account of several aspects of the obligational framework, in particular the role of doubting responses and the ubiquity of obligational vocabulary in the context of scientific discourse in the medieval tradition.
Flesh and Nature: Understanding Merleau-Ponty’s Relational Ontology
Authors: Bannon Bryan E.
Published: October 2011

In this paper I attempt to develop several ways Merleau-Ponty’s ontology might contribute to an environmental ethic through a redefinition of his concept of flesh in terms of a general theory of affectivity. Currently accepted interpretations of the concept such as those in Abram, Toadvine, Barbaras, and Dastur rely upon conceiving flesh as a perceptual experience. I contest this interpretation and argue that a more productive conception of flesh emerges when understood in terms of Heidegger’s philosophy. The paper concludes with a consideration of the normative significance of flesh by examining the role of “wildness” within a place-based ethic.
Prophets of the Round Table: The Protestant Church in the Netherlands and the Public Domain
Authors: de Lange Frits
Published: October 2011

In the current Dutch public debate on the public role of religion, three political options are defended: secularism, pacified pluralism and social cohesionism. They correspond to three types of ecclesiology: the church as witness, the church as a platform of moral deliberation and the church as a community of moral formation. In the document ‘The Church and the Democratic Constitutional State’ (2009) the Protestant Church in the Netherlands (PCN) set out its vision on its own public role. The church is presented as ‘prophet at the round table’; a combination of the first two types of ecclesiology. It results in a ‘polder-ecclesiology’, fully understandable within the Dutch context of a radically secularized, democratic constitutional state, but probably inadequate as a response to its reigning political, ethnic and social instability.
The Silent Scream of a Silenced History:Part Two: Church Responses
Authors: Prior John Mansford
Published: October 2011

Part One of this paper looked at local Church responses to the massacre in the Maumere district of central Flores, Indonesia, during the months of February to April 1966. Instigated by the Indonesian army, the slaughter of from 800 to 2,000 people was implemented by local Catholics against victims who were also Catholic. Responses of the local clergy, Archbishop and Dean are studied together with an account by one of the perpetrators, and the memoirs of three Dutch missioners written 40 years after the event. In Part Two these responses are examined in the light of two analyses of the Indonesian Church, one using an ‘integration’ frame, the other a Volkskirche model. When combined these studies allow us to begin to comprehend how the massacre could happen and why the clergy responded as they did. Honesty and transparency would allow us to move forward in mission with ‘bold humility’.
Fighting for Jesus on Ambon: Interpreting Religious Representations of Violent Conflict
Authors: van Liere Lucien M.
Published: October 2011

Between 1999 and 2002 religion-related riots took place on the Maluku islands in Indonesia. After the first clash, in January 1999, the conflict disseminated rapidly along religious lines. Religious language was used in order to understand what was going on, inscribing the conflict into specific religious traditions. However, using religious language to understand the conflict also framed the conflict into an essentialist religious battle with an important religious meaning. In this article I will explore the possibility to understand the religious framing of this conflict as a religious variety of what Vamik Volkan has coined ‘chosen trauma’. Applying this term to the situation in Ambon, elucidates the impact of religious language on violent conflicts.
Recent Advances in the Understanding of Near-Cloud Turbulence
Authors: Lane Todd P. , Sharman Robert D. , Trier Stanley B. , Fovell Robert G. , Williams John K.
Published: October 2011

Anyone who has flown in a commercial aircraft is familiar with turbulence. Unexpected encounters with turbulence pose a safety risk to airline passengers and crew, can occasionally damage aircraft, and indirectly increase the cost of air travel. Deep convective clouds are one of the most important sources of turbulence. Cloud-induced turbulence can occur both within clouds and in the surrounding clear air. Turbulence associated with but outside of clouds is of particular concern because it is more difficult to discern using standard hazard identification technologies (e.g., satellite and radar) and thus is often the source of unexpected turbulence encounters. Although operational guidelines for avoiding near-cloud turbulence exist, they are in many ways inadequate because they were developed before the governing dynamical processes were understood. Recently, there have been significant advances in the understanding of the dynamics of near-cloud turbulence. Using examples, this article demonstrates how these advances have stemmed from improved turbulence observing and reporting systems, the establishment of archives of turbulence encounters, detailed case studies, and high-resolution numerical simulations. Some of the important phenomena that have recently been identified as contributing to near-cloud turbulence include atmospheric wave breaking, unstable upper-level thunderstorm outflows, shearing instabilities, and cirrus cloud bands. The consequences of these phenomena for developing new en route turbulence avoidance guidelines and forecasting methods are discussed, along with outstanding research questions.
Retinol Binding Protein
Authors: Kraft Robert , Herndon David N. , Kulp Gabriela A. , Mecott Gabriel A. , Trentzsch Heiko , Jeschke Marc G.
Published: October 2011

Introduction: Burn injury leads to vast changes in both metabolic and inflammatory responses and is associated with increased morbidity and mortality. Insulin resistance (IR) and hyperglycemia are major components of the hypermetabolic response found in burn‐injured patients and subsequently contribute to adverse outcomes. Studies have shown that increased systemic retinol binding protein (RBP) levels are associated with IR and hyperinflammation in diabetic and obese patients. The aim of this study was to determine RBP profiles and to test the hypothesis that elevated RBP levels are associated with both IR and the inflammatory response in burned patients. Methods: RBP was measured in 372 patients during the acute stay postburn. Patients' demographics, glucose levels, and insulin administration were recorded. Cytokines, hormones, plasma proteins, and organ markers were measured. The average of all measurements of RBP (2.1 mg/dL) was used to divide patients into high and low groups. Statistical analysis was performed by Student t test. Statistical significance was accepted at P < .05. Results: Fifty‐one patients (high group) had elevated RBP levels during acute hospitalization and demonstrated a significant higher incidence of multiorgan failure, sepsis, and mortality (P < .05). Moreover, in the high group, a significant increase of IR, inflammatory cytokines, and catabolic and organ‐specific markers were detected (P < .05). Conclusions: Increased RBP levels postburn correlate with increased IR, inflammatory and catabolic responses, incidence of multiorgan failure, and mortality. RBP may be a novel biomarker to monitor these detrimental responses postburn.
The Effect of Early Enteral Nutrition on Hyperthermic Intraoperative Intraperitoneal Chemotherapy–Induced Mucosal Permeability Following Gastrectomy
Authors: Li Gang , Gu Rongmin , Wen Xu , Wei Da , Ming Xuezhi , Chen Huanqiu
Published: October 2011

Aim: To investigate (1) the effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) on intestinal permeability of patients with advanced gastric cancer and (2) the protective effect of postoperative enteral nutrition (EN) on patients. Methods: >All patients were divided randomly into 3 groups: the EN group, treated with EN during postoperative period; the EN+HIIC group, treated with HIIC and postoperative EN; and the PN+HIIC group, treated with HIIC and postoperative parenteral nutrition. The lactulose/mannitol (L/M) ratio was used to evaluate the permeability of intestinal mucous. Results: Compared with the ratio of L/M on the day before operation (POD‐1), the ratio of L/M on POD+3 increased significantly in all 3 groups (P < .0001) and then decreased gradually. The L/M ratio of the EN and EN+HIIC groups recovered to the baseline on POD+12. In contrast, the PN+HIIC group still had an elevated L/M ratio until POD+12. The ratios of L/M in the EN+HIIC group on POD+7 and POD+12 were significantly different from those of the PN+HIIC group (0.0855 ± 0.0462 vs 0.1298 ± 0.063, P = .007; 0.0336 ± 0.0235 vs 0.0616 ± 0.0430, P = .038, respectively). Conclusion: Gastric cancer radical resection resulted in a significant increase in intestinal permeability. HIIC aggravated the injury of intestinal mucous permeability, which could be reversed by EN.
Docosahexaenoic Acid and Arachidonic Acid Prevent Essential Fatty Acid Deficiency and Hepatic Steatosis
Authors: Le Hau D. , Meisel Jonathan A. , de Meijer Vincent E. , Fallon Erica M. , Gura Kathleen M. , Nose Vania , Bistrian Bruce R. , Puder Mark
Published: October 2011

Objectives: Essential fatty acids are important for growth, development, and physiologic function. α‐Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. Methods: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. Results: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. Conclusion: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without α‐linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model.
Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice
Authors: Budni Josiane , Lobato Kelly R , Binfaré Ricardo W , Freitas Andiara E , Costa Ana Paula , Martín-de-Saavedra Maria Dolores , Leal Rodrigo B , Lopez Manuela G , Rodrigues Ana Lúcia S
Published: October 2011

Preclinical and clinical studies indicate that deficiency in folic acid plays a role in the pathophysiology of depression. Considering that alterations in the signaling pathways that regulate neuroplasticity and cellular survival are implicated in depressive disorders, the present study investigated the involvement of the phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3 (GSK-3β), and peroxisome proliferator-activated receptor-γ (PPARγ) in the antidepressant-like effect of folic acid in the forced swimming test (FST). The intracerebroventricular (i.c.v.) pre-treatment of mice with LY294002 (10 nmol/site, a PI3K inhibitor) or GW-9662 (1 µg/site, a PPARγ antagonist) prevented the antidepressant-like effect of folic acid (50 mg/kg, p.o.) in the FST. In addition, the administration of subeffective doses of the selective GSK-3β inhibitor, AR-A014418 (3 mg/kg, i.p.), a non-selective GSK-3β inhibitor, lithium chloride (10 mg/kg, p.o) or a PPARγ agonist, rosiglitazone (1 µg/site, i.c.v.) in combination with a subeffective dose of folic acid (10 mg/kg, p.o.) significantly reduced the immobility time in the FST as compared with either drug alone, without altering the locomotor activity. These results indicate that the antidepressant-like effect of folic acid in the FST might be dependent on inhibition of GSK-3β and activation of PPARγ, reinforcing the notion that these are important targets for antidepressant activity.
Are Emerging Markets Relevant for Portfolio Diversification?
Authors: Kumar S.S.S.
Published: October 2011

In the recent financial meltdown, along with the slump in developed markets, emerging markets also declined sharply, bringing into doubt their ability to provide diversification benefits. One of the stylised facts of volatility is its negative correlation with the equity market, which in conjunction with the launching of securities for trading volatility, leads to the emergence of a new asset class for portfolio diversification. From the perspective of investors in the US, this study investigates whether a domestic portfolio along with exposure to an alternative asset class like volatility index (VIX) fares better than investing in emerging markets. The results show that for the minimum variance portfolios, there is a significant increase in Sharpe ratio when VIX is included, instead of the emerging markets to the domestic portfolio. Adding VIX is bene-ficial, as the magnitude and direction of its correlation is not only predictable but also stable. While the emerging markets correlations with developed markets are positive and increasing thereby diminish-ing the diversification benefits. Hence, US investors in pursuit of risk reduction have an alternative investment opportunity in volatility-based contracts.
Food Aid, External Trade and Domestic Markets
Authors: Dorosh Paul A. , Subran Ludovic
Published: October 2011

In the last decade, internal conflict has greatly hindered market transactions across regions of Sudan, especially transactions between Darfur and the rest of Sudan. Food aid has helped to offset not only the absence of commercial inflows of grain, but also reductions in Darfur’s cereal production. This article explores the determinants of cereal prices in Sudan utilising a simple partial equilibrium framework for wheat and sorghum, the country’s two main food staples. We also present econometric evidence on the lack of integration of sorghum markets between Darfur and central Sudan, along with quantitative estimates of the impacts of food aid on market prices in the region. The article concludes with a discussion of national food policy and the paradox of simultaneous commercial exports and large-scale food aid imports of sorghum.
Optimisation of electrochemical stripping of galvannealed interstitial free steels
Authors: Paranhos R M V , Lins V F C , Waldemar A A M , Alvarenga E A
Published: October 2011

Hot dip galvanised steels with thermal treatment or galvannealed steels are used in automotive industries because of their properties of weldability, workability and corrosion resistance. The galvannealed steels show three iron–zinc phases: zeta, delta and gamma. The distribution and concentration of iron–zinc phases affect the quality of the zinc layer and can produce stamping and welding problems. In the present work, the optimisation study of the electrochemical stripping process of industrial galvannealed steel was performed. The effect of electrolyte, pH, current density and scan rate was evaluated. The best resolution of the potential levels in the electrochemical dissolution curves was obtained for the zinc sulphate heptahydrate and sodium chloride aqueous solution, with a current density of 2 mA cm−2 and pH 4·5. Each sample surface obtained by using electrochemical stripping was analysed using X-ray diffraction and scanning electron microscopy.
Unusually high current efficiency of nanocrystalline Cr electrodeposition process from trivalent chromium bath
Authors: Protsenko V S , Gordiienko V O , Danilov F I , Kwon S C , Kim M , Lee J Y
Published: October 2011

A sulphate trivalent chromium bath was described which contains 1M Cr(III) as well as carbamide and formic acid as complexing agents. The introduction of NaF into the bath was shown to result in increasing the current efficiency of chromium electrodeposition up to uncommonly high values (∼50%). The trivalent chromium bath proposed allows obtaining bright and smooth nanocrystalline Cr coatings with a thickness of several tens micrometres.
Electroless deposition of Co–Mo–P alloys
Authors: Rudnik E , Mucha M
Published: October 2011

Influence of the concentration (0–1×10−3M) of Mo(IV) compounds on the electroless deposition of Co–Mo–P alloy from alkaline citrate bath was investigated. The changes of the plating potential, mass of the deposits and hydrogen evolution as well as composition and morphology of the deposits with the concentration of additives were determined. Similar behaviour was observed for all compounds. Increase in the [Formula: see text] concentration in the bath was accompanied by inhibition of Co–Mo–P deposition and only traces of deposits were obtained at 1×10−3M Mo(VI). Molybdenum content in the deposits was low and oxygen was detected in the layers produced at 5×10−4 and 1×10−3M Mo(VI). Such changes corresponded to a gradual evolution of the morphology of the deposits from needle to fine grained structure, but Na2MoO4 produced deposits of the best quality. Adsorption of [Formula: see text] ions at the metal/electrolyte interface was proposed as responsible for phenomena observed in the Co–Mo–P system.
Colouring of anodised aluminium by electroless method
Authors: Selvam M
Published: October 2011

In this investigation, a porous oxide coating has been formed on aluminium using direct current anodising technique, sensitised in stannous ion followed by colouring in dilute silver ion at different concentrations and durations to produce pleasing colours ranging from yellow to brown and black. The metallically coloured surface has been analysed using EDAX, atomic force microscopy, X-ray diffraction and ultraviolet–visible–infrared spectrophotometer, and a suitable mechanism has been proposed.
Electrodeposition of biopolymer–glucose oxidase composites
Authors: Li Y , Zhitomirsky I
Published: October 2011

Composite films containing glucose oxidase in a biopolymer matrix were prepared by electrodeposition. Chitosan–glucose oxidase films were prepared by cathodic electrodeposition. Anodic electrodeposition method was developed for the deposition of alginic acid and hyaluronic acid films containing glucose oxidase. The proposed deposition mechanisms involved electrophoresis, pH changes at the electrode surfaces attributed to electrochemical reactions, coagulation of polymer macromolecules and glucose oxidase and film formation. The deposition yield was studied as a function of biopolymer and glucose oxidase concentration in the solutions. The results of the deposition yield measurements, Fourier transform infrared spectroscopy and thermogravimetric and differential thermal analyses showed the formation of composite films. Electron microscopy studies showed that the film thickness can be varied in the range of 0–3 μm by the variation in deposition time at a constant deposition voltage. The methods enabled the formation of uniform films of controlled thickness. The electrodeposition methods can be used for the fabrication of biosensors.
A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma
Authors: Bieging Kathryn T. , Fish Kamonwan , Bondada Subbarao , Longnecker Richard
Published: October 2011

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed. We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells.
Regulation of murine hematopoietic stem cell quiescence by Dmtf1
Authors: Kobayashi Michihiro , Srour Edward F.
Published: October 2011

The cell-cycle status of hematopoietic stem cells (HSCs) is tightly regulated, most likely to balance maintenance of stem-cell status through quiescence and expansion/differentiation of the hematopoietic system. Tumor-suppressor genes (TSGs), with their cell cycle–regulatory functions, play important roles in HSC regulation. The cyclin-D binding myb-like transcription factor 1 (Dmtf1) was recently recognized as a TSG involved in human cancers by repressing oncogenic Ras/Raf signaling. However, the role of Dmtf1 in the hematopoietic system is entirely unknown. In the present study, we demonstrate that Dmtf1 regulates HSC function under both steady-state and stress conditions. Dmtf1−/− mice showed increased blood cell counts in multiple parameters, and their progenitor cells had increased proliferation and accelerated cell-cycle progression. In addition, long-term HSCs from Dmtf1−/− mice had a higher self-renewal capacity that was clearly demonstrated in secondary recipients in serial transplantation studies. Dmtf1−/− BM cells showed hyper proliferation after 5-fluorouracil–induced myeloablation. Steady-state expression and Induction of CDKN1a (p21) and Arf were impaired in HSCs from Dmtf1−/− mice. The function of Dmtf1 was mediated by both Arf-dependent and Arf-independent pathways. Our results implicate Dmtf1 in the regulation of HSC function through novel cell cycle–regulatory mechanisms.
Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase
Authors: Landfried Karin , Zhu Wentao , Waldhier Magdalena C. , Schulz Ute , Ammer Julia , Holler Barbara , Wolff Daniel , Edinger Matthias , Peter Katrin , Kreutz Marina , Andreesen Reinhard , Oefner Peter J. , Holler Ernst
Published: October 2011

Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 ± 0.3 μmol/mmol creatinine in the absence of acute GVHD, 8.0 ± 1.1 μmol/mmol creatinine for GVHD grade 1 or 2, and 13.5 ± 2.7 μmol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation.
IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo
Authors: Recher Mike , Berglund Lucinda J. , Avery Danielle T. , Cowan Morton J. , Gennery Andrew R. , Smart Joanne , Peake Jane , Wong Melanie , Pai Sung-Yun , Baxi Sachin , Walter Jolan E. , Palendira Umaimainthan , Tangye Gillian A. , Rice Michael , Brothers Shannon , Al-Herz Waleed , Oettgen Hans , Eibel Hermann , Puck Jennifer M. , Cattaneo Federica , Ziegler John B. , Giliani Silvia , Tangye Stuart G. , Notarangelo Luigi D.
Published: October 2011

SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21–mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.
Lymph node B lymphocyte trafficking is constrained by anatomy and highly dependent upon chemoattractant desensitization
Authors: Park Chung , Hwang Il-Young , Sinha Rajesh K. , Kamenyeva Olena , Davis Michael D. , Kehrl John H.
Published: October 2011

B lymphocyte recirculation through lymph nodes (LNs) requires crossing endothelial barriers and chemoattractant-triggered cell migration. Here we show how LN anatomy and chemoattractant receptor signaling organize B lymphocyte LN trafficking. Blood-borne B cells predominately used CCR7 signaling to adhere to high endothelial venules (HEVs). New B cell emigrants slowly transited the HEV perivenule space, and thereafter localized nearby, avoiding the follicle. Eventually, the newly arrived B cells entered the basal portion of the follicle gradually populating it. In contrast, newly arriving activated B cells rapidly crossed HEVs and migrated toward the lymph node follicle. During their LN residency, recirculating B cells reacquired their sphingosine-1 phospate receptor 1 (S1P1) receptors and markedly attenuated their sensitivity to chemokines. Eventually, the B cells exited the LN follicle by entering the cortical lymphatics or returning to the paracortical cords. Upon entering the lymph, the B cells lost their polarity, down-regulated their S1P1 receptors, and subsequently strongly up-regulated their sensitivity to chemokines. These results are summarized in a model of homeostatic trafficking of B cells through LNs.
Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness
Authors: Rossi Davide , Bruscaggin Alessio , Spina Valeria , Rasi Silvia , Khiabanian Hossein , Messina Monica , Fangazio Marco , Vaisitti Tiziana , Monti Sara , Chiaretti Sabina , Guarini Anna , Del Giudice Ilaria , Cerri Michaela , Cresta Stefania , Deambrogi Clara , Gargiulo Ernesto , Gattei Valter , Forconi Francesco , Bertoni Francesco , Deaglio Silvia , Rabadan Raul , Pasqualucci Laura , Foà Robin , Dalla-Favera Riccardo , Gaidano Gianluca
Published: October 2011

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P = .046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL.
Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV
Authors: Fabarius Alice , Leitner Armin , Hochhaus Andreas , Müller Martin C. , Hanfstein Benjamin , Haferlach Claudia , Göhring Gudrun , Schlegelberger Brigitte , Jotterand Martine , Reiter Andreas , Jung-Munkwitz Susanne , Proetel Ulrike , Schwaab Juliana , Hofmann Wolf-Karsten , Schubert Jörg , Einsele Hermann , Ho Anthony D. , Falge Christiane , Kanz Lothar , Neubauer Andreas , Kneba Michael , Stegelmann Frank , Pfreundschuh Michael , Waller Cornelius F. , Spiekermann Karsten , Baerlocher Gabriela M. , Lauseker Michael , Pfirrmann Markus , Hasford Joerg , Saussele Susanne , Hehlmann Rüdiger ,   for the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the German CML Study Group
Published: October 2011

The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome–positive (Ph+) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (−Y) and 41 patients (3.6%) had ACAs except −Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), −Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.
The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study
Authors: Hedley Paula L , Haundrup Ole , Andersen Paal S , Aidt Frederik H , Jensen Morten , Moolman-Smook Johanna C , Bundgaard Henning , Christiansen Michael
Published: October 2011

Background

The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic disease associated with an improper hypertrophic response.

Results

The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls.

Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only.

Conclusions

Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmia