129 research outputs found
Natalia Ginzburg. «Scrivere con il corpo» sul margine del «buco del Reale»
No full textIn this article, we aim at describing the relationship between the body and the writing within the literary production of Natalia Ginzburg (1916-1991) by relying on some ermeneutical tools from the lacanian psychoanalysis. In the first part of the article - The Language and the Unconscious - we describe the nature of the lacanian subject, divided between the subjective word and the linguistical structure, between the self and the illusion of the self. Those are two poles divided by an opacity which is intrinsic to the existence, which cannot be resolved by language, nor by writing. The second part - The fragmentation as a narrative and psychoanalytical tool - investigates the ways in which Natalia Ginzburg assumed on herself the responsibility of this splitting, transforming it in the container - and content - of her entire narrative. On the one hand, the fracture emerges through the use of fragmentation, in the different voices experimented by Ginzburg between 1942 and 1984. On the other hand, this fracture becomes a psychoanalytical-existential tool to investigate the problematic relationship between the subject and the world. Each time the narrator or the characters (do not) take the word is symptomatic of a highly personal void, which differs based on the stories being told. We will try to bring the multiplicity of these subjects back to unity by means of some of the pathosformeln described by Lacan, shedding new light on them. In the third part - Writing with the body - we summarize the strategies devised by the author to answer her biographic enjeux, which consists in being capable of writing notwithstanding the sadness arising from the relationship with the «hole of the Real». Each word carved by the pen of Natalia Ginzburg takes consciousness of the untouchability of life and represents an act of love towards the «opacity of the wording underlying the statements deriving from it».Quest’articolo si propone di illustrare il legame tra corpo e scrittura che caratterizza la parabola creativa di Natalia Ginzburg (1916-1991) attraverso alcuni strumenti ermeneutici della psicanalisi lacaniana. Nella prima parte dell’articolo - Linguaggio e Inconscio - si definisce la natura del soggetto lacaniano, scisso tra parola soggettiva e struttura linguistica, tra il sé e l’illusione del sé: due poli divisi da un’opacità connaturata all’esistenza, che il linguaggio e la scrittura non possono risolvere. La seconda parte - La frammentazione come strumento narrativo e psicanalitico – indaga i modi in cui Natalia Ginzburg ha assunto su di sé la responsabilità di questa scissione trasformandola in contenente e contenuto di tutta la sua narrativa: da un lato, la frattura si manifesta tramite lo strumento della frammentazione, nelle diverse voci sperimentate dalla Ginzburg fra il 1942 e il 1984; dall’altro, la crepa diventa strumento psicanalitico-esistenziale per l’indagine del rapporto problematico tra soggetto e mondo. Ogni (non) presa di parola da parte dell’autrice o dei suoi personaggi è sintomo di un vuoto personalissimo e sempre diverso a seconda delle storie raccontate. Tenteremo di ricondurre la molteplicità di questi soggetti scissi all’unità tramite alcune delle pathosformeln descritte da Lacan, investendole di nuova luce. Nella terza parte - Scrivere con il corpo - si riassumono le strategie elaborate dalla scrittrice per rispondere al suo enjeux biografico, ovvero riuscire a scrivere malgrado l’infelicità causata dal rapporto con il «buco del Reale». Ogni parola vergata dalla penna di Natalia Ginzburg è una presa d’atto dell’intangibilità della vita e un atto di amore verso «l’opacità dell’enunciazione che soggiace agli enunciati che ne derivano».
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In this article, we aim to describe the relationship between the body and the writing within the literary production of Natalia Ginzburg (1916-1991) by relying on some ermeneutical tools from the lacanian psychoanalysis. In the first part of the article - The Language and the Unconscious - we describe the nature of the lacanian subject, divided between the subjective word and the linguistical structure, between the self and the illusion of the self. Those are two poles divided by an opacity which is intrinsic to the existence, which cannot be resolved by language, nor by writing. The second part - The fragmentation as a narrative and psychoanalytical tool - investigates the ways in which Natalia Ginzburg assumed on herself the responsibility of this splitting, transforming it in the container - and content - of her entire narrative. On the one hand, the fracture emerges through the use of fragmentation, in the different voices experimented by Ginzburg between 1942 and 1984. On the other hand, this fracture becomes a psychoanalytical-existential tool to investigate the problematic relationship between the subject and the world. Each time the narrator or the characters (do not) take the word is symptomatic of a highly personal void, which differs based on the stories being told. We will try to bring the multiplicity of these subjects back to unity by means of some of the pathosformeln described by Lacan, shedding new light on them. In the third part - Writing with the body - we summarize the strategies devised by the author to answer her biographic enjeux, which consists in being capable of writing notwithstanding the sadness arising from the relationship with the «hole of the Real». Each word carved by the pen of Natalia Ginzburg takes consciousness of the untouchability of life and represents an act of love towards the «opacity of the wording underlying the statements deriving from it»
Cronache di integrazione. Viaggio tra le criticità di un’accoglienza tutta italiana
No full textThe author analyses some aspects of the Italian reception system through a case study of
a life story, exemplary in highlighting the difficulties, limitations and beauty of an existence in transit.
The system will be outlined in its historical and legal components, in accordance with the new provisions in force, to create a clear and complete picture. The many initiatives of entities supporting the
system will equally be recognized as part of the path to empowerment and autonomy for those who
arrive in Italy eager to build their future here. The goal will be to be able to contribute to the complex
discourse that is generated around the figure of the migrant, in the hope that the multi-ethnic society
of which we are already a part of will be built daily with awareness, and that it will not remain utopistic in its best manifestation
Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab
No full textBackground: Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients. Methods: In this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel's C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival. Results: Our results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression-free survival was 2.6months [95% confidence interval (CI) 1.9-3.3] in patients with high sCD73 enzyme activity (>27.8pmol/min/mg protein), and 14.2months (95% CI 4.6-23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24months range. The median overall survival was not reached in patients with low sCD73 activity (<27.8pmol/min/mg protein) compared with 6.1months (95% CI 0-14.8) in patients with higher sCD73 activity. In multivariate analyses, the sCD73 enzyme activity emerged as the strongest prognostic factor for overall survival and progression-free survival. Elevated basal levels of sCD73 enzyme activity, before starting nivolumab treatment, were associated with lower response rates to therapy. Conclusions: We observed a significant association between the activity of sCD73 in the blood and clinical outcomes in patients with metastatic melanoma stage IV, receiving nivolumab. Although our results need to be confirmed and validated, we suggest that sCD73 might be used as serologic prognostic biomarker. Potentially evaluating sCD73 enzyme activity in the peripheral blood before treatment could help to estimate the response to nivolumab
Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes trough downregulation of intermediate filament nestin
No full textVittorio Castaldo1, Michele Minopoli2, Francesca Di Modugno3, Andrea Sacconi4, Domenico Liguoro5, Rachele Frigerio6, Arianna Ortolano6, Marta Di Martile7, Luisa Gesualdi5, Gabriele Madonna8, Mariaelena Capone8, Roberto Cirombella9, Angiolina Catizone1, Donatella Del Bufalo7, Andrea Vecchione9, Maria Vincenza Carriero2, Paolo Antonio Ascierto8, Rita Mancini5,9, Luigi Fattore*6, Gennaro Ciliberto10.
1 Department of Anatomy, Histology, Forensic- Medicine and Orthopedics, Sapienza University of Rome, 00161, Rome, Italy.
2 Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', 80131 Naples, Italy.
3 Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Via Chianesi 53, 00144 Rome, Italy.
4 Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
5 Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.
6 SAFU Laboratory, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
7 Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
8 Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131, Naples, Italy
9 Faculty of Medicine and Psychology, Department Clinical and Molecular Medicine, Sant’Andrea Hospital-Sapienza University of Rome, 00118, Rome, Italy
10 Scientific Directorate, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy.
Abstract
Background and rationale: BRAF-mutant melanoma patients benefit from the combinatorial treatments with BRAF and MEK inhibitors. However, acquired drug resistance strongly limits the efficacy of these targeted therapies in time. Recently, many findings have underscored the involvement of microRNAs as main drivers of drug resistance. In this context, we previously identified a subset of oncomiRs strongly up-regulated in drug-resistant melanomas. In this work, we shed light on the molecular role of two as yet poorly characterized oncomiRs, miR-4443 and miR-4488.
Methods: Invasion and migration have been determined by wound healing, Boyden chamber, transwell invasion assays and Real Time Cell Analysis (RTCA) technology. miR-4488 and miR-4443 have been measured by qRT-PCR. Nestin levels have been tested by immunofluorescence immunohistochemical and flow cytometry analyses.
Results: We demonstrate that the two oncomiRs are responsible for the enhanced migration and invasive phenotypes, that are a hallmark of drug resistant melanoma cells. Moreover, miR-4443 and miR-4488 promote an aberrant cytoskeletal reorganization witnessed by the increased number of stress fibers and cellular protrusions-like cancer cell invadopodia. Mechanistically, we have identified the intermediate filament nestin as a molecular target of both oncomiRs. Finally, we have shown that nestin levels are able to predict response to treatments in melanoma patients.
Conclusions: Altogether these findings have profound translational implications in the attempt i) to develop miRNA-targeting therapies to mitigate the metastatic phenotypes of BRAF-mutant melanomas and ii) to identify novel biomarkers able to guide clinical decisions
Main roads to melanoma
No full textThe characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underlying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects regarding the main molecular changes responsible for the onset as well as the progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying the pathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of down- or up-regulation of various effectors acting on different molecular pathways
Role of the androgen receptor in melanoma aggressiveness.
No full textMalignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting
receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall
survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As
such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female
advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role
of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We
now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killermediated
cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the
androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the
androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a
poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells
depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors,
suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as
a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients
Activating PIK3CA mutations coexist with BRAF or NRAS mutations in a limited fraction of melanomas
No full textBackground: Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples. Methods: A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing. Results: Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations. Conclusions: Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma
ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma. Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin
No full textIn recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy
Innate Immune Cells in Melanoma: Implications for Immunotherapy
No full textThe innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients’ clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy
Enzyme activity of circulating CD73 in human serum
No full textCD73 is an ectonucleotidase able to catabolize 5′-adenosine monophosphate (AMP) into adenosine at the extracellular level. Extracellular adenosine plays a critical role in regulating many processes under physiological and pathological conditions. In the context of cancer, the expression and activity of CD73, either in tissue and in biological fluids, is increased leading to high levels of adenosine that potently suppress T-cell mediated responses, promoting tumor progression through stimulation of adenosine receptors. Compelling evidence indicates that elevated levels of CD73-generating adenosine limit the efficacy of cancer immunotherapy. Inhibitors of ectonucleotidases and antagonists of adenosine receptors have emerged as new therapeutic tools to improve anti-tumor immune response and potentially synergize with currently used immunotherapeutic agents. Measurement of CD73 levels in serum of cancer patients is a promising approach that, although it needs to be validated, may help to select patients who will benefit from adenosine-targeting agents and predict response to immunotherapy. Here, we describe a simple and fast method to evaluate the AMPase activity of CD73 in peripheral blood that may also be applied to other biological fluids
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