1,720,969 research outputs found
Complement as a biological tool to control tumor growth
Full text linkDeposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation. The aim of this review is to discuss the protective role of complement in cancer with special focus on the beneficial effect of complement-fixing antibodies that are efficient activators of the classical pathway and contribute to inhibit tumor expansion as a result of MAC-mediated cancer cell killing and complement-mediated inflammatory process. Cancer cells are heterogeneous in their susceptibility to complement-induced killing that generally depends on stable and relatively high expression of the antigen and the ability of therapeutic antibodies to activate complement. A new generation of monoclonal antibodies are being developed with structural modification leading to hexamer formation and enhanced complement activation. An important progress in cancer immunotherapy has been made with the generation of bispecific antibodies targeting tumor antigens and able to neutralize complement regulators overexpressed on cancer cells. A great effort is being devoted to implementing combined therapy of traditional approaches based on surgery, chemotherapy and radiotherapy and complement-fixing therapeutic antibodies. An effective control of tumor growth by complement is likely to be obtained on residual cancer cells following conventional therapy to reduce the tumor mass, prevent recurrences and avoid disabilities
Biological Features of Nanoparticles: Protein Corona Formation and Interaction with the Immune System
Full text linkNanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is hindered by their undesirable recognition by the immune system and the consequent immunotoxicity, as well as their rapid clearance in vivo. After injection, NPs are usually covered with layers of proteins, called protein coronas (PCs), which alter their identity, biodistribution, half-life, and efficacy. Therefore, the characterization of the PC is for in predicting the fate of NPs in vivo. The aim of this review was to summarize the state of the art regarding the intrinsic factors closely related to the NP structure, and extrinsic factors that govern PC formation in vitro. In addition, well-known opsonins, including complement, immunoglobulins, fibrinogen, and dysopsonins, such as histidine-rich glycoprotein, apolipoproteins, and albumin, are described in relation to their role in NP detection by immune cells. Particular emphasis is placed on their role in mediating the interaction of NPs with innate and adaptive immune cells. Finally, strategies to reduce PC formation are discussed in detail
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
USE OF IMMUNE-NANOPARTICLES CONTAINING CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF B-CELL MALIGNANCIES
Full text link2013/2014B-cell malignancies are a heterogeneous group of clinical conditions including indolent diseases such as Chronic Lymphocytic Leukemia (CLL) and highly aggressive lymphoproliferative disorders such as Burkitt’s lymphoma.
B-cell malignancies treatments take advantage of dose-intensive chemotherapeutic regimens and immunotherapy via monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents and cause several adverse effects. Thus, we propose a novel therapeutic approach for the treatment of CLL and Burkitt’s lymphoma in which high-doses of the association of hydroxychloroquine and chlorambucil (HCQ/CLB) or fludarabine were loaded inside biodegradable nanoparticles (BNPs) coated with an anti-CD20 antibody.
First of all, a Burkitt’s lymphoma cell line (BJAB), two CLL cell lines (MEC1 and EHEB) and cells purified from patients’ blood samples were used to confirm CD20 expression and to assess BNPs binding and internalization. These studies demonstrated BNPs ability to bind malignant B cells and to enter inside cells in a process different from endocytosis. Then, BNPs therapeutic effect was evaluated by MTT test, AnnV/PI assay and western blot to put in evidence apoptosis induction and autophagy inhibition. These experiments demonstrated drugs-loaded BNPs ability to kill malignant B cells with comparable effects than those obtained with free drugs whereas empty BNPs were practically ineffective.
In vivo BNPs characterization included the evaluation of their toxicity, biodistribution and therapeutic effect. C57/BL mice were used to evaluate BNPs toxicity which was studied considering survival, loss of body weight and several tissue markers in the blood. Mice receiving 8 injections of free HCQ+CLB died in this experiment whereas animals challenged with the same amount of drugs encapsulated inside BNPs did not show toxic effects suggesting BNPs safety.
The importance of antiCD20 antibody in the homing of BNPs was confirmed by in vivo Time-Domain Optical Imaging performed in localized B-cell malignancy-bearing mice. This analysis suggested the ability of antiCD20-conjugated BNPs to specifically target tumor B-cells, with a pick after 24-48 hours. On the contrary, untargeted BNPs localization inside tumor was significantly decreased. In this analysis it was also evident that the liver is the main site of BNPs’ elimination while in the other organs the presence of fluorescent BNPs was very low.
Finally, BNPs ability to treat a new xenograft human/SCID leukemia and Burkitt’s lymphoma mouse model was studied. Drugs-loaded BNPs were able to improve HCQ/CLB efficacy in vivo allowing the cure of treated all Burkitt’s lymphoma-bearing mice and 3 out of 7 leukemia-bearing animals.
All these data together put the basis for the potential use of BNPs in the treatment of B-cell malignancies.I tumori a cellule B sono un gruppo eterogeneo di patologie che comprendono sia malattie indolenti, come la leucemia linfatica cronica (LLC), sia aggressive, come il linfoma di Burkitt. Il trattamento delle patologie a cellule B prevede sia l’utilizzo di chemioterapici (agenti alchilanti e analoghi delle purine) che di anticorpi monoclonali. Nonostante la varietà di terapie esistenti, l’efficacia di questi farmaci è limitata dalla mancata specificità per le cellule tumorali e dall’induzione di gravi effetti collaterali. Per ovviare ai limiti delle terapie attuali, è stato quindi proposto l’utilizzo di nanoparticelle coniugate con un anticorpo antiCD20, specifico per le cellule B, e contenenti alte concentrazioni di chemioterapici (idrossiclorochina e clorambucile o fludarabina). Le nanoparticelle sono state caratterizzate in vitro e in vivo durante questo progetto di dottorato.
Inizialmente sono stati effettuati studi in vitro al fine di valutare l’espressione del CD20 sulla superficie di una linea cellulare di linforma di Burkitt (BJAB), due linee di LLC (MEC1 e EHEB) e cellule purificate da campioni di sangue di pazienti affetti da LLC. In seguito, il legame e l’internalizzazione delle nanoparticelle a queste cellule sono stati dimostrati suggerendo anche come le nanoparticelle vengano internalizzate attraverso un meccanismo diverso dall’endocitosi.
L’effetto terapeutico in vitro delle nanoparticelle è stato valutato con test MTT, AnnessinaV/PI e tramite western blot al fine di evidenziare l’induzione di apoptosi e l’inibizione dell’autofagia, meccanismi attraverso cui i farmaci utilizzati sono noti agire. Questi esperimenti hanno dimostrato che le nanoparticelle cariche di chemioterapici sono in grado di uccidere le cellule B tumorali con effetti paragonabili a quelli ottenuti da pari concentrazioni di farmaci liberi dimostrando come il processo di produzione delle nanoparticelle non influisca sull’efficacia dei chemioterapici. Al contrario, nanoparticelle vuote non sono in grado di uccidere le cellule dimostrando la mancata tossicità dei polimeri da cui sono costituite. Dopo aver confermato il legame e l’internalizzazione delle nanoparticelle che inducono la morte delle cellule B tumorali, sono stati effettuati esperimenti in vivo tra cui studi di tossicità al fine di valutare eventuali effetti collaterali indotti dal trattamento, studi di biodistribuzione e la valutazione degli effetti terapeutici.
Gli studi di tossicità sono stati effettuati in topi sani valutando parametri quali la perdita di peso, la sopravvivenza e la tossicità sistemica. Nanoparticelle cariche di
farmaci presentano un profilo tossicologico sicuro mentre pari dosi di farmaci liberi inducono la morte di tutti gli animali trattati. Questi esperimenti dimostrano quindi come l’inserimento di farmaci all’interno di nanoparticelle prevenga gli effetti collaterali normalmente indotti dai chemioterapici. Secondariamente, sono stati effettuati studi di biodistribuzione di nanoparticelle coniugate o meno con un anticorpo antiCD20. Questi studi effettuati tramite Optical Imaging dimostrano come nanoparticelle coniugate con l’anticorpo antiCD20 si localizzino preferenzialmente nella massa tumorale in 24-48 ore in quantità maggiore rispetto a nanoparticelle non coniugate con l’anticorpo. Inoltre, da queste analisi risulta evidente come il fegato sia il maggiore sito di eliminazione delle nanoparticelle mentre in altri organi la presenza di nanoparticelle è molto bassa.
Infine, un modello disseminato di linfoma di Burkitt e un modello di LLC sono stati sviluppati in topi SCID (Severe Combined ImmunoDeficiency) iniettando rispettivamente cellule BJAB intraperitoneo e cellule MEC1 endovena. I modelli sono stati caratterizzati e utilizzati per valutare la potenziale applicazione delle nanoparticelle nel trattamento di queste patologie. Questi studi hanno dimostrato come le nanoparticelle siano in grado di aumentare l’efficacia dei chemioterapici e di curare tutti i topi affetti da linfoma di Burkitt e 3/7 topi affetti da leucemia.
Concludendo, questi risultati suggeriscono la potenziale applicazione delle nanoparticelle cariche di chemioterapici nel trattamento di LLC e linfoma di Burkitt.XXVII Ciclo198
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