71 research outputs found
ORIGINAL RESEARCH Light Chain Amyloidosis: Patient Experience Survey from the Amyloidosis Research Consortium
No full textThe Author(s) 2015. This article is published with open access at Springerlink.com Introduction: Information detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges i
Phillipsite at high pressure: a single-crystal X-ray synchrotron diffraction study
No full textPhillipsite is a low Si/Al natural zeolite, often found as autogenic mineral in both “close” and “open” hydrologic system or in vugs of basalt, as an alteration product of volcanic glass. Along with laumontite, it is one of the most common zeolites found in oceanic basalts. In order to investigate the high-pressure behavior of phillipsite and its structural evolution at the atomic scale, we performed an in situ single-crystal synchrotron X-ray diffraction experiment up to 10 GPa with a diamond anvil cell, using a nominally penetrating pressure-transmitting fluid (methanol:ethanol:H2O = 16:3:1 mix) (Gatta, 2010). The unit-cell parameters and the structure refinements within the P-range investigated show that: 1) phillipsite does not adsorb further H2O molecules from the penetrating-transmitting fluid within the P-range investigated; 2) the configuration of the extra-framework population changes with pressure (between 2 and 3 GPa), affecting the elastic behavior of the mineral. More in details, two distinct compressional regimes have been observed, in which the bulk moduli differs drastically (i.e., KV = 89(8) GPa between 0 and 2 GPa, KV = 18.8(7) GPa between 3 and 9 GPa); 3) phillipsite is crystalline at least up to 10 GPa, and this is surprising if we consider its microporous nature; 4) all the P-induced effects are completely reversible in decompression. The structural refinements allowed us to describe the mechanisms, at the atomic scale, that govern its elastic behavior, which are mainly governed by inter-tetrahedral tilting. The relatively low compressibility of phillipsite at room-P and its relatively wide P-stability shown in this experiment suggests that this zeolite is a potential H2O carrier during the first phase of the oceanic crust subduction or, toward the industrial front, its potential
use in systems for the mechanical energy storage/dissipation (Eroshenko et al., 2001; Soulard et al., 2004).
Acknowledgements: The author acknowledges the Italian Ministry of Education, MIUR-Project: “Futuro in
Ricerca 2012 - ImPACT- RBFR12CLQD”
C-Finite Sequences and Riordan Arrays
No full textMany prominent combinatorial sequences, such as the Fibonacci, Lucas, Pell, Jacobsthal and Tribonacci sequences, are defined by homogeneous linear recurrence relations with constant coefficients. These sequences are often referred to as C-finite sequences, and a variety of representations have been employed throughout the literature, largely influenced by the author’s background and the specific application under consideration. Beyond the representation through recurrence relations, other approaches include those based on generating functions, explicit formulas, matrix exponentiation, the method of undetermined coefficients and several others. Among these, the generating function approach is particularly prevalent in enumerative combinatorics due to its versatility and widespread use. The primary objective of this work is to introduce an alternative representation grounded in the theory of Riordan arrays. This representation provides a general formula expressed in terms of the vectors of constants and initial conditions associated with any recurrence relation of a given order, offering a new perspective on the structure of such sequences
A mutation-based radiomics signature predicts response to imatinib in Gastrointestinal Stromal Tumors (GIST)
No full textObjectives: To develop a mutation-based radiomics signature to predict response to imatinib in Gastrointestinal Stromal Tumors (GISTs). Methods: Eighty-two patients with GIST were enrolled in this retrospective study, including 52 patients from one center that were used to develop the model, and 30 patients from a second center to validate it. Reference standard was the mutational status of tyrosine-protein kinase (KIT) and platelet-derived growth factor α (PDGFRA). Patients were dichotomized in imatinib sensitive (group 0 - mutation in KIT or PDGFRA, different from exon 18-D842V), and imatinib non-responsive (group 1 - PDGFRA exon 18-D842V mutation or absence of mutation in KIT/PDGFRA). Initially, 107 texture features were extracted from the tumor masks of baseline computed tomography scans. Different machine learning methods were then implemented to select the best combination of features for the development of the radiomics signature. Results: The best performance was obtained with the 5 features selected by the ANOVA model and the Bayes classifier, using a threshold of 0.36. With this setting the radiomics signature had an accuracy and precision for sensitive patients of 82 % (95 % CI:60–95) and 90 % (95 % CI:73–97), respectively. Conversely, a precision of 80 % (95 % CI:34–97) was obtained in non-responsive patients using a threshold of 0.9. Indeed, with the latter setting 4 patients out of 5 were correctly predicted as non-responders. Conclusions: The results are a first step towards using radiomics to improve the management of patients with GIST, especially when tumor tissue is unavailable for molecular analysis or when molecular profiling is inconclusive
Functional correlates of N-terminal natriuretic peptide type B (NT-proBNP) response to therapy in cardiac light chain (AL) amyloidosis
No full textIn cardiac (light chain) AL amyloidosis, a decrease in circulating free light chains (FLCs) higher than 50% is associated with reduced N-terminal natriuretic peptide type B (NT-proBNP) serum concentration, improvement of heart failure symptoms, and prolonged survival. To assess the functional correlates of these changes, echocardiographic indices of systolic and diastolic regional function were compared at diagnosis and after response achievement in 32 patients. FLCs and NT-proBNP were concomitantly measured. No significant change in left ventricular wall thicknesses, chamber dimensions, indices of diastolic dysfunction or ejection fraction was observed after chemotherapy. In contrast, systolic longitudinal excursion of both the interventricular septum and the lateral wall was increased (from 5.2 +1.4 to 6.8 +1.5 and from 6.2 +1.3 to 7.7 +1.4 mm, respectively; p50.05 for both). These changes were significantly correlated with the extent of FLCs (p=0.05) and NT-proBNP (p=0.05) reduction. In cardiac AL amyloidosis, hematological response to chemotherapy and reduction of cardiac biomarkers are associated with improved indices of regional systolic functioavailabl
Daily variation of brain-derived neurotrophic factor and cortisol in women with normal menstrual cycles, undergoing oral contraception and in postmenopause
No full textBACKGROUND: Plasma brain-derived neurotrophic factor (BDNF) levels are associated with the hormonal status of women. Moreover, the suprachiasmatic nucleus appears to be implicated in the modulation of BDNF central levels. We aimed to investigate whether BDNF circadian rhythms exist in women and if there is a relationship with cortisol circadian rhythmicity. Moreover, we aimed to establish whether the hormonal status influences BDNF diurnal variations. METHODS: A total of 30 women were studied: 10 fertile ovulatory women, 10 women undergoing oral contraceptive (OC) therapy and 10 post-menopausal women. Basal BDNF and estradiol levels were assayed in blood samples collected after overnight fasting at regular intervals (08:00, 12:00, 16:00, 20:00, 24:00). BDNF and cortisol levels were measured in samples collected during the follicular and luteal phases in ovulatory women and once a month in OC and post-menopausal women. RESULTS: Luteal BDNF levels were significantly higher than follicular levels in fertile women (P < 0.001). In OC women, BDNF levels were similar to the follicular BDNF levels, whereas in post-menopausal women, they were significantly lower (P < 0.001). BDNF showed a diurnal rhythm in the follicular phase and in women undergoing OC, although the diurnal rhythm was blunted in the luteal phase. In post-menopausal women, BDNF and cortisol levels significantly decreased during the day. CONCLUSIONS: BDNF has a diurnal variation in women that is somewhat analogous to cortisol variation; however, the amplitude of the variation in BDNF levels appears to be influenced by ovarian function. Interactions between BDNF, the hypothalamus-pituitary-adrenal axis and sex steroids might play a critical role in the human homeostasis and adaptation. © The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved
Freedom paradox: the reflection of being free in the social pact of Jean-Jacques Rousseau
No full textFilósofo e romancista, Jean-Jacques Rousseau (1712-1778) pode ser considerado como um dos autores mais complexos da filosofia política. Buscando resolver a grande questão dessa área, a saber, como o Estado pode ser legitimado, Rousseau argumenta em prol de uma teoria do pacto, buscando justificar a existência do Estado enquanto uma instituição artificial, fundada pelos próprios homens. Apoiado na natureza humana, Rousseau tem por finalidade argumentar por que os homens devem se submeter ao Estado e de que forma isso lhes seria vantajoso. Tentando convencer os homens das benesses do estado civil, Rousseau faz um longo estudo sobre a questão da liberdade, desde sua forma mais primitiva, vivida pelo homem no estado de natureza contido no Segundo discurso, à sua forma mais evoluída, no estado civil, apresentada no Contrato social. Esse artigo se propõe a analisar a construção teórica do que seria ser livre nos dois momentos propostos por Rousseau, com o objetivo de explicitar como esse conceito é capaz de basear a argumentação do autor.Philosopher and novelist, Jean-Jacques Rousseau (1712-1778) can be considered one of the most complex authors of political philosophy. Seeking to solve the great question of this area, that is how the State can be legitimized, Rousseau argues for a theory of the pact, trying to justify the existence of the State as an artificial institution, founded by men. Supported by human nature, Rousseau’s purpose is to argue why men should submit themselves to the State and how it would be good to them. Trying to convince men of the benefits of civil status, Rousseau make a long study about the question of freedom, from its most primitive form, lived by man in the state of nature contained in the Second discourse, untilits most evolved for, in the civil state, presented in the Social contract. This article proposes to analyze the theoretical construction of what would be to be free in the two moments proposed by Rousseau, with the objective of explaining how this concept is able to base the argument of the author
SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides
No full textSARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neuron
CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes
No full textPurpose: No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes in vitro and in immunodeficient mice.Experimental Design: The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored in vitro, in two- and three-dimensional STS cultures, and in three in vivo STS xenograft models.Results: CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by in silico analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior in vitro cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in vivo in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK.Conclusions: This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes in vitro and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting
Authorship and the Discovery of Character in Medieval Romance
No full textThis dissertation argues that by pioneering new ways of constructing and reading literary character, writers of twelfth- to fourteenth-century romance also claimed a new authority for vernacular fiction. Through readings of several key medieval texts, the dissertation not only illuminates character as an underestimated critical tool used by medieval writers in but also intervenes in the ongoing scholarly discussion of medieval authorship. It begins with Le Roman d’Enéas, a twelfth-century adaptation of Virgil’s Aeneid that, by revising tensions in the characters of the Latin royal court, familiarizes the epic for a courtly audience and posits its writer as an authoritative interpreter of the Aeneid. Next, medieval concepts of memory and contemporary serial narrative theory are used to argue that Chrétien de Troyes, inventor of French Arthurian romance, creates a model of character that requires audiences to read his romances as a corpus and thus establishes himself as the author of a new literary tradition. Chapter 3 narrows its focus to a single character, Merlin, in Geoffrey of Monmouth’s Vita Merlini, Laȝamon’s Brut, and Of Arthour and of Merlin, arguing that Merlin proves a useful site for examining tensions of gender and national identity inherent in the act of transforming legend into written historical narrative. The dissertation concludes with Geoffrey Chaucer’s Troilus and Criseyde. It demonstrates that in his portrayals of Antigone and Cassandra as literary creators, Chaucer examines the problem of affective identification with literary characters, questioning the association of compassion and femininity and offering alternative models of authorship.Doctor of Philosoph
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