Covariate comportamentali della tossicodipendenza da eroina. Correlazione con la percezione soggettiva di craving.

Il Craving, definibile come il desiderio incoercibile nei confronti di una sostanza, costituirebbe un'entità psicopatologica che è il core del Disordine da Uso di Sostanze. Nonostante la sua chiara rilevanza clinica, ad oggi non esistono scale di valutazione che indaghino gli aspetti qualitativi del craving da eroina, mentre sono presenti solo alcuni strumenti di indagine volti all’identificazione del craving dal punto di vista meramente quantitativo. In letteratura, esiste un’immotivata mancanza di studi delle covariate comportamentali del craving da eroina nei soggetti eroinomani. Questa tesi si propone di valutare la presenza e la severità di differenti comportamenti addictivi in 114 pazienti con Disturbo da Uso di Eroina (HUD) in trattamento con agonisti oppiacei, correlando a livello multivariato la presenza e severità soggettiva del craving con i comportamenti legati all’uso di eroina. Da questo studio è emerso come l’autovalutazione che i pazienti tossicodipendenti da eroina rivolgono al proprio craving, è connessa alla centralità dei pensieri riguardanti l’eroina, alla questione della scelta di eroina al posto di qualsiasi altra fonte di gratificazione e allo sforzo necessario per ottenere la sostanza in questione. Gli stessi eroinomani non riconoscono invece come espressione di craving per l’eroina la pratica della condivisione di siringhe potenzialmente infette, l'uso della sostanza e le ricadute indotte da stimuli ambientali droga-correlati. E' pertanto plausibile ritenere che indagare e riconoscere tali comportamenti debba essere di basilare interesse clinico al fine di un'adeguata analisi del craving e di un’implementazione dell’approccio terapeutico volto al miglioramento dell’outcome

The magnocellular-dorsal pathway dysfunction in developmental dyslexia: Case-control, longitudinal and intervention studies

Reading is a unique cognitive human skill crucial to life in modern societies, but for about 10% of children, learning to read is extremely difficult. These children are affected by developmental dyslexia (DD). Although the most common explanation of DD suggest a specific disorder in auditory and phonological processing, several studies show that also a magnocellular-dorsal (MD) pathway dysfunction could be a core deficit in DD. In this thesis will be investigated the MD functioning on children with and without DD by two case-control studies. The causal relationship between MD dysfunction and reading impairment will be investigated through: (i) two longitudinal studies, in which the attentional skills was tested in pre-reading children, and (ii) five intervention studies in which children with DD was treated with a visual-attentional training (i.e., action video game, AVG). The MD functioning was tested with different tasks that are able to capture different skills driven by MD pathway. In particular, the low spatial frequency, processed by MD pathway, will be investigated through Navon tasks in which is important the global perception of the scene. Another aspect linked to the MD pathway, is the signal-to-noise exclusion in which the target is processed filtering the noise, and this will be investigated through a crowding task and visual and auditory attentional noise exclusion tasks. The findings show that the MD functioning is impaired already at pre-reading stage in future poor readers and that AVG training is able to improve reading speed and attentional skills linked to the MD pathway functioning. For these reason it will be sustain the causal role of MD pathway dysfunction in DD, and the DD as a multifactorial neurodevelopmental disorder

Long Non-Coding RNAs as Molecular Signatures for Canine B-Cell Lymphoma Characterization

Background: Diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL) and follicular lymphoma (FL) are the most common B-cell lymphomas (BCL) in dogs. Recent investigations have demonstrated overlaps of these histotypes with the human counterparts, including clinical presentation, biologic behavior, tumor genetics, and treatment response. The molecular mechanisms that underlie canine BCL are still unknown and new studies to improve diagnosis, therapy, and the utilization of canine species as spontaneous animal tumor models are undeniably needed. Recent work using human DLBCL transcriptomes has suggested that long non-coding RNAs (lncRNAs) play a key role in lymphoma pathogenesis and pinpointed a restricted number of lncRNAs as potential targets for further studies. Results: To expand the knowledge of non-coding molecules involved in canine BCL, we used transcriptomes obtained from a cohort of 62 dogs with newly-diagnosed multicentric DLBCL, MZL and FL that had undergone complete staging work-up and were treated with chemotherapy or chemo-immunotherapy. We developed a customized R pipeline performing a transcriptome assembly by multiple algorithms to uncover novel lncRNAs, and delineate genome-wide expression of unannotated and annotated lncRNAs. Our pipeline also included a new package for high performance system biology analysis, which detects high-scoring network biological neighborhoods to identify functional modules. Moreover, our customized pipeline quantified the expression of novel and annotated lncRNAs, allowing us to subtype DLBCLs into two main groups. The DLBCL subtypes showed statistically different survivals, indicating the potential use of lncRNAs as prognostic biomarkers in future studies. Conclusions: In this manuscript, we describe the methodology used to identify lncRNAs that differentiate B-cell lymphoma subtypes and we interpreted the biological and clinical values of the results. We inferred the potential functions of lncRNAs to obtain a comprehensive and integrative insight that highlights their impact in this neoplasm

Dnmt3a restrains mast cell inflammatory responses

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation

Novel GC-rich DNA-binding compound produced by a genetically engineered mutant of the mithramycin producer Streptomyces argillaceus exhibits improved transcriptional repressor activity: implications for cancer therapy

The aureolic acid antibiotic mithramycin (MTM) binds selectively to GC-rich DNA sequences and blocks preferentially binding of proteins, like Sp1 transcription factors, to GC-rich elements in gene promoters. Genetic approaches can be applied to alter the MTM biosynthetic pathway in the producing microorganism and obtain new products with improved pharmacological properties. Here, we report on a new analog, MTM SDK, obtained by targeted gene inactivation of the ketoreductase MtmW catalyzing the last step in MTM biosynthesis. SDK exhibited greater activity as transcriptional inhibitor compared to MTM. SDK was a potent inhibitor of Sp1-dependent reporter activity and interfered minimally with reporters of other transcription factors, indicating that it retained a high degree of selectivity toward GC-rich DNA-binding transcription factors. RT–PCR and microarray analysis showed that SDK repressed transcription of multiple genes implicated in critical aspects of cancer development and progression, including cell cycle, apoptosis, migration, invasion and angiogenesis, consistent with the pleiotropic role of Sp1 family transcription factors. SDK inhibited proliferation and was a potent inducer of apoptosis in ovarian cancer cells while it had minimal effects on viability of normal cells. The new MTM derivative SDK could be an effective agent for treatment of cancer and other diseases with abnormal expression or activity of GC-rich DNA-binding transcription factors

End-to-End Assembly of Shape-Controlled Nanocrystals via a Nanowelding Approach Mediated by Gold Domains.

[*] Dr. A. Figuerola, I. R. Franchini, A. Fiore, Dr. S. Kudera, Prof. R. Cingolani, Dr. L. Manna National Nanotechnology Laboratory of CNR-INFM, Unita di Ricerca IIT Distretto Tecnologico ISUFI, via per Arnesano km 5, I-73100 Lecce (Italy) Fax: (þ39) 0832298237 E-mail: [email protected] Dr. A. Figuerola, A. Fiore, R. Mastria, Prof. R. Cingolani Scuola Superiore ISUFI; University of Salento Distretto Tecnologico ISUFI, via per Arnesano km 5, I-73100 Lecce (Italy

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients

Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib