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Nuovi approcci terapeutici del carcinoma corticosurrenalico: effetto del rosiglitazone e studio del ruolo di p53 nella risposta al trattamento con radiazioni ionizzanti
Get PDFIl carcinoma corticosurrenalico (ACC) è una rara forma di tumore endocrino, la cui prognosi è variabile, a seconda dallo stadio del tumore e dal momento della diagnosi, ma generalmente infausta. L’esatta e-ziopatogenesi dell’ACC non è ancora stata del tutto chiarita, tuttavia alcuni importanti fattori di rischio sono rappresentati dalla perdita di funzione di p53 e dall’over-espressione di IGF2 e VEGF. Le terapie attualmente disponibili per la cura di questa neoplasia non risultano completamente efficaci e la variabilità nella risposta ai diversi trattamenti è estremamente elevata.
Lo scopo del lavoro svolto durante il Dottorato di Ricerca era di migliorare le attuali conoscenze relative al-le possibili opzioni terapeutiche del carcinoma corticosurrenalico. Tale obiettivo è stato perseguito attraverso due diversi tipi di approccio: da un lato, la valutazione degli effetti anti-neoplastici del rosiglitazone, un far-maco insulino-sensibilizzante, in due linee cellulari derivanti da ACC, al fine di determinarne l’efficacia tera-peutica; dall’altro, la valutazione del ruolo dell’onco-soppressore p53 nella risposta alla radioterapia, con l’obiettivo di dimostrarne la validità come fattore predittivo per la risposta a questo tipo di trattamento.
L’effetto anti-tumorale del rosiglitazone è stato testato in due linee cellulari di carcinoma corticosurrenalico, H295R e SW-13, isolate rispettivamente da un carcinoma al II stadio secernente e da un tumore al IV stadio non secernente. I risultati ottenuti hanno dimostrato l’efficacia del rosiglitazone nell’inibire la proliferazione di queste linee cellulari. Lo studio dei meccanismi molecolari alla base dell’effetto del farmaco ha inoltre evi-denziato due diversi meccanismi d’azione, che consistono nell’induzione di morte per autofagia nella linea H295R e nell’arresto della proliferazione correlato alla de-regolazione del ciclo cellulare nelle cellule SW-13.
Lo studio del ruolo di p53 nella risposta alla radioterapia ha dimostrato l’importanza della corretta funziona-lità di questo fattore per l’inibizione della proliferazione e l’induzione della morte per apoptosi in seguito a questo trattamento, evidenziando inoltre un forte effetto di inibizione sulla via di trasduzione del segnale me-diata da IGF-II e Akt.
La valutazione dello stato dell’oncogene HIF-1 nei due modelli cellulari di ACC ha dimostrato l’iper-attivazione di questo fattore. Il ripristino della funzione di p53 appare in grado di inibire l’espressione di HIF-1α in seguito all’irraggiamento, determinando inoltre una diminuzione nei livelli di VEGF-A.
I risultati finora raggiunti, pertanto, indicano l’efficacia del rosiglitazone nella terapia per il carcinoma corti-cosurrenalico e dimostrano il ruolo fondamentale di p53 wild type per la risposta al trattamento radioterapico, suggerendone l’importanza come fattore terapeutico e predittivo. Essi inoltre indicano HIF-1α come un poten-ziale nuovo oncogene per il carcinoma corticosurrenalico, di grande importanza come marker diagnostico e target terapeutico
Current and emerging therapeutic options in adrenocortical cancer treatment.
No full textAdrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30 and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia. © 2012 Antonio Stigliano et al
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation
No full textMitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11β-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10-5 M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability
Variations on the Author
Get PDF“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
Bloch surface waves biosensors for high sensitivity detection of soluble ERBB2 in a complex biological environment
No full textWe report on the use of one-dimensional photonic crystals to detect clinically relevant concentrations of the cancer biomarker ERBB2 in cell lysates. Overexpression of the ERBB2 protein is associated with aggressive breast cancer subtypes. To detect soluble ERBB2, we developed an optical set-up which operates in both label-free and fluorescence modes. The detection approach makes use of a sandwich assay, in which the one-dimensional photonic crystals sustaining Bloch surface waves are modified with monoclonal antibodies, in order to guarantee high specificity during the biological
recognition. We present the results of exemplary protein G based label-free assays in complex biological matrices, reaching an estimated limit of detection of 0.5 ng/mL. On-chip and chip-to-chip variability of the results is addressed too, providing repeatability rates. Moreover, results on fluorescence operation demonstrate the capability to perform high sensitive cancer biomarker assays reaching a resolution of 0.6 ng/mL, without protein G assistance. The resolution obtained in both modes meets international guidelines and recommendations (15 ng/mL) for ERBB2 quantification assays, providing an alternative tool to phenotype and diagnose molecular cancer subtypes
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines
No full textC-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro-caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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
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