bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

AbstractThis 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

AbstractMaimonides 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

AbstractIt 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

AbstractAristotle 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

AbstractThis 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

AbstractIn 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

AbstractIn 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.
The Silent Scream of a Silenced History:Part Two: Church Responses
Authors: Prior John Mansford 
Published: October 2011

AbstractPart 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

AbstractBetween 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.
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

AbstractThe 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

AbstractThe 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

Abstract
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

AbstractSCID 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.