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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
161

Analisi molecolare delle fasi evolutive della micosi fungoide / Evolution of mycosis fungoides: molecular analysis

Fiorani, Roberta <1980> 16 April 2013 (has links)
Lo scopo del progetto triennale del dottorato di ricerca è lo studio delle alterazioni genetiche in un gruppo di pazienti affetti da micosi fungoide ed un gruppo di pazienti affetti da sindrome di Sezary. Dalle biopsie cutanee è stato estratto il DNA e analizzato, comparandolo con DNA sano di riferimento, utilizzando la tecnica array-CGH, allo scopo di identificare la presenza di geni potenzialmente implicati nel processo di oncogenesi. Questa analisi è stata eseguita, per ogni paziente, su biopsie effettuate ad una fase iniziale di malattia e ad una fase di progressione della stessa. Sugli stessi pazienti è stata inoltre eseguita un’analisi miRNA. Si ipotizza che il profilo d’espressione dei miRNA possa infatti dare informazioni utili per predire lo stato di malattia, il decorso clinico, la progressione tumorale e la riposta terapeutica. Questo lavoro è stato poi eseguito su biopsie effettuate in pazienti affetti da sindrome di Sezary che, quando non insorge primitivamente come tale, si può considerare una fase evolutiva della micosi fungoide. La valutazione delle alterazioni genetiche, ed in particolare la correlazione esistente tra duplicazione e delezione genetica e sovra/sottoespressione genetica, è stata possibile attraverso l’interpretazione e la comparazione dei dati ottenuti attraverso le tecniche array-CGH e miRNA. Sono stati comparati i risultati ottenuti per valutare quali fossero le alterazioni cromosomiche riscontrate nei diversi stadi di malattia. L’applicazione dell’array-CGH e della metodica di analisi mi-RNA si sono rivelate molto utili per l’identificazione delle diverse aberrazioni cromosomiche presenti nel genoma dei pazienti affetti da micosi fungoide e sindrome di Sezary, per valutare la prognosi del paziente e per cercare di migliorare o trovare nuove linee terapeutiche per il trattamento delle due patologie. Lo studio di questi profili può rappresentare quindi uno strumento di grande importanza nella classificazione e nella diagnosi dei tumori. / The purpose of the project of research is the study of genetic alterations in a group of patients with mycosis fungoides and a group of patients with Sezary syndrome. From skin biopsies DNA was extracted and analyzed, comparing it with healthy DNA of reference, using the technique array-CGH, in order to identify the presence of genes potentially involved in the process of oncogenesis. This analysis was performed for each patient, on biopsies taken at an early stage of disease and to a phase of progression thereof. On the same patients was also carried out an analysis of miRNAs. It is hypothesized that the expression profile of miRNA can in fact provide useful information to predict disease status, clinical course, tumor progression and therapeutic response. This work was then done on biopsies performed in patients with Sezary syndrome, which can be considered as a single entity or a developmental stage of mycosis fungoides. The evaluation of genetic alterations, and in particular the correlation between genetic deletion and duplication and over / subexpression of genes, has been made possible through the interpretation and comparison of data obtained through the techniques array-CGH and miRNA. We compared the results obtained to assess what were the chromosomal alterations found in different stages of disease. The application of the method and array-CGH analysis of mi-RNA proved to be very useful for the identification of several chromosomal aberrations present in the genome of patients with mycosis fungoides and Sezary syndrome, to evaluate the prognosis of the patient and to try to improve or find new lines therapeutic for the treatment of two diseases. The study of these profiles may therefore represent a tool of great importance in the classification and diagnosis of cancer.
162

Studio della via di segnale PI3K/Akt/mTOR nelle Cellule Dendritiche / Study of the PI3K/Akt/mTOR signaling pathway of Dendritic Cells

Ulbar, Francesca <1983> 06 June 2013 (has links)
Il trapianto allogenico di cellule staminali emopoietiche è spesso l’unica soluzione per la cura di diverse malattie ematologiche. La aGVHD è la complicanza più importante che si può avere a seguito del trapianto allogenico ed è causata dai linfociti T del donatore che riconoscono gli antigeni del ricevente presentati dalle APC. Eliminare o inattivare la APC del ricevente prima del trapianto potrebbe prevenire la aGVHD. Ad oggi non esistono farmaci specifici diretti contro le APC, sono però noti i meccanismi molecolari coinvolti nella sopravvivenza cellulare come la via di segnale di PI3K. In questo lavoro abbiamo testato l’attività di due farmaci, che colpiscono target molecolari della via di PI3K, la rapamicina e la perifosina, sul differenziamento dei monociti a differenti popolazioni di cellule dendritiche (DC), in vitro. La rapamicina riduceva il recupero cellulare delle DC derivate da monociti coltivate in presenza di IL-4 aumentando l’apoptosi, mentre i monociti coltivati in presenza di GM-CSF con o senza IFN-α risultavano resistenti alla rapamicina. Inoltre la rapamicina riduceva l’espressione della molecola costimolatoria CD86 e incrementava l’espressione della molecola CD1a solo nei monociti coltivati con GM-CSF e IL-4. Nelle DC derivate dai monociti in presenza di IL-4 la rapamicina bloccava la produzione di IL-12 e TNF-α e ne alterava la capacità allostimolatoria. La rapamicina non alterava la sopravvivenza e la funzione delle DC circolanti. Il trattamento con perifosina provocava un incremento di apoptosi nei monociti coltivati sia con GM-CSF che con GM-CSF e IL-4. La perifosina bloccava la produzione di TNF-α nelle DC derivate da monociti coltivati nelle diverse condizioni. Questi risultati dimostrano che l’azione della rapamicina è strettamente dipendente dalla presenza dell’IL-4 nel terreno di coltura, in vitro, rispetto alla perifosina e suggeriscono un possibile ruolo della perifosina nella prevenzione della GVHD prima del trapianto allogenico di cellule staminali. / Allogeneic transplantation of hematopoietic stem cells (HTSC) is the most effective curative option for many neoplastic hematological disease. Acute graft versus host disease (aGVHD) is the most feared complication following HTSC and is caused by donor lymphocytes recognizing recipient histocompatibility antigen presented by antigen-presenting cells (APC). Removal or inactivation of APC before transplantation prevents GVHD. Nowadays there are no drugs specifically targeting APC. The molecular mechanisms involved in cell growth of these cells are well known and mostly involve the activation of the PI3K signaling pathway. In this study we tested the effects of two drugs targeting the PI3K pathway, rapamycin and perifosine on the differentiation of monocytes to distinct DC subtypes in vitro. Rapamycin decreased the recovery of monocyte-derived DC cultured in presence of IL-4 due to increased apoptosis, while monocytes cultured in GM-CSF with or without IFN-α were not affected. Rapamycin decreased the expression of the costimulatory molecules CD86 and increased the expression of CD1a in monocyte-derived DC, only in presence of IL-4. Moreover, rapamycin blocked the secretion of IL-12 and TNF-α and altered the allostimulatory capacity only in monocytes cultured with IL-4. Rapamycin didn’t alter the survival and function of circulating DC. Treatment with perifosine was associated with increased apoptosis of monocytes cultured both with GM-CSF only or with GM-CSF and IL-4. Perifosine blocked the secretion of TNF-α by monocytes cultured with GM-CSF only and with GM-CSF and IL-4 after 3 days of culture. These results suggest that the action of rapamycin is more strictly dependent on IL-4 than perifosine, suggesting a possible use of perifosine in the prevention of GVHD before HSCT.
163

The KIT gene in familial mastocytosis / Il gene KIT nella mastocitosi familiare

Tourlaki, Athanasia <1973> 16 April 2013 (has links)
Familial cutaneous mastocytosis is an exceptional condition of unknown etiology. In this study we report the largest series of patients with familial cutaneous mastocytosis without other manifestations (18 affected subjects from seven unrelated families), and we investigate the role of germ-line KIT mutations in the pathogenesis of the disease. The mean age at onset was 5.4 years (range from birth to 22 years), and the clinical behavior was variable over a mean follow up period of 15.1 years (range 2-36): improvement in seven, stability in eight and worsening in the remaining three patients. The pattern of inheritance was compatible with an autosomal dominant trait with incomplete penetrance; a female preponderance (14 females vs 4 males, ratio 3.5:1) was noted; among the six women who have been pregnant at least once, three experienced important clinical changes during pregnancy. No germ-line mutation was found in the exons 10, 11, and 17 of the KIT proto-oncogene, which are the most commonly mutated exons in sporadic mastocytosis. However, in the majority of affected subjects we found the Met541Leu polymorphic variant of the KIT gene, which seems to confer a growth advantage to mast cells in vitro. This observation further suggests that the Met541Leu may be a predisposing factor of cutaneous mastocytosis, although it seems to be neither necessary nor sufficient for the development of the disease.
164

Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias / Sviluppo pre-clinico e clinico di inibitori della cellula staminale leucemica nelle leucemie acute

Papayannidis, Cristina <1980> 06 June 2013 (has links)
In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.
165

Correlation between insulin resistance and treatment-resistant acne

Maffeis, Laura <1981> 16 April 2013 (has links)
Physiologically during puberty and adolescence, when juvenile acne usually appears, the response to a glucose load is increased if compared to the one observed in adult and at pre-pubertal age, while insulin sensitivity is reduced. Insulin is a hormone that acts at different levels along the axis which controls the sex hormones. It increases the release of LH and FSH by pituitary gland, stimulates the synthesis of androgens in the gonads and stimulates the synthesis of androgenic precursors in adrenal glands. Finally, it acts in the liver by inhibiting the synthesis of Sex Hormone Binding Globulin (SHBG). Insulin is also able to act directly on the production of sebum and amplify the effects of Iinsulin Growth Factor-1 in the skin, inhibiting the synthesis of its binding protein (IGF Binding Protein-1). In female subjects with acne and Polycystic Ovary Syndrome (PCOS) insulin resistance is a well known pathogenetic factor, while the relationship between acne and insulin resistance has been poorly investigated in males so far. The purpose of this study is to investigate the correlation between insulin resistance and acne in young males who do not respond to common therapies. Clinical and biochemical parameters of glucose, lipid metabolism, androgens and IGF-1 were evaluated. Insulin resistance was estimated by Homeostasis Model assessment (HOMA-IR) and Oral Glucose Tolerance Test was also performed. We found that subjects with acne had higher Sistolic and Diastolic Blood Pressure, Waist/Hip Ratio, Waist Circumference, 120' OGTT serum insulin and serum IGF-1 and lower HDL-cholesterol than subjects of comparable age and gender without acne. The results thus obtained confirmed what other authors have recently reported about a metabolic imbalance in young males with acne. Furthermore, these results support the hypothesis that insulin resistance might play an important role in the pathogenesis of treatment-resistant acne in males.
166

Studio dei polimorfismi genici degli antigeni minori di istocompatibilità e GvHD/GvL nel trapianto allogenico di cellule staminali emopoietiche / Multi-genotyping of minor histocompatibility antigens (mHAgs) to study graft versus host disease (GvHD) and graft versus leukemia (GvL) effects in allogeneic stem cell transplantation

Cattina, Federica <1983> 06 June 2013 (has links)
L'outcome dei pazienti sottoposti a trapianto allogenico di cellule staminali emopoietiche è fortemente influenzato da graft versus leukemia (GvL) e graft versus host disease (GvHD) che sono mediate, almeno in parte, dagli antigeni minori di istocompatibilità (mHAgs). In letteratura sono stati identificati 26 mHAgs che sono stati correlati a GvHD/GvL con risultati incompleti e in alcuni casi contrastanti; inoltre manca una metodica che sia in grado di genotipizzare contemporaneamente un pannello così ampio. Il lavoro è stato finalizzato alla preparazione di un protocollo di laboratorio che permetta di studiare in modo efficace i 26 mHAgs identificati, per poi correlarli con GvHD/GvL all’interno di uno specifico gruppo di trapiantati. Utilizzando la metodica IPlex Gold Mass Array Sequenom e tecniche di biologia molecolare convenzionale sono stati genotipizzati 26 antigeni minori di istocompatibilità per 46 coppie full-matched. Tutti i pazienti inclusi nel progetto di studio erano stati sottoposti a trapianto allogenico di cellule staminali emopoietiche da donatore familiare o volontario full-compatibile per leucemia mieloide cronica (n=46) o leucemia acuta linfoblastica Philadelphia positiva (LAL-Ph+, n=24). Il progetto ha confermato l'efficienza (98.6%) e la fattibilità delle metodiche proposte. Dal lavoro è inoltre emerso che, le differenze tra donatore e ricevente a libello mHAgs ACC-1, ACC-4, ACC-5, LB-MTHFD1-1Q, UGT2B17, DPH1, LRH1 potrebbero essere fattori predittivi di GvHD (p<0.05). La seconda evidenza è legata a un trend secondo cui il mismatch per LB-ADIR1 protegge dalla recidiva di malattia, in particolare nei confronti della LAL-Ph+ che è scarsamente responsiva all'allo-immunoterapia. Questo lavoro pilota, la cui casistica deve quindi essere ampliata, ha dimostrato l’efficacia della genotipizzazione con IPlex Gold Sequenom e l’elevato potenziale degli mHAgs sia come fattori predittivi di GvHD che come driver di GvL. / The outcome of allogeneic stem cell transplantation (Allo-SCT) is closely related to graft versus host disease (GvHD) and graft versus leukemia (GvL) effects which, in part, are mediated by mHAgs. Twenty-six mHAgs have been identified and reported to be differently and variably correlated with GVHD or GVL, but a simultaneous method to genotype a so large panel of mHAgs has never been employed. The aim of this work has been to develop a feasible method to genotype all the 26 mHAgs described so far and to test them for their correlation with GVHD and GVL in a group of donor/recipient pairs submitted to allo-SCT. For a multi-genotyping of 23 mHAgs we used iPlex Gold Mass Array technology (3 multiplex). For the other three mHAgs we designed other three assays based on conventional molecular biology. By these methods, we tested the 26 mHAgs in 46 donor/recipient pairs full-matched that underwent allo-SCT (sibling or MUD) because of Philadelphia positive CML (n=46) or ALL-Ph+ (n=24). Maldi-Tof IPlex Gold technology proved a high degree of efficiency (98.6%). As expected, sibling pairs showed most identity of MUD pairs. Notably, donor/recipient mismatch on ACC-1, ACC-4, ACC-5, LB-MTHFD1-1Q, UGT2B17, DPH1, LRH1 can drive GvHD effect (p<0.01). Next we identified that LB-ADIR1 can enhance (p=ns, but there is a trend) GvL effect specially on ALL-Ph+ that is otherwise un-responsible to allo-immunotherapy. Our data generated by a multi-genotype technique confirm the role of mHAgs in addressing GvL (in some cases without GvHD) and suggest that a study of mHAgs could be perfomed before transplant in order to better investigate the role of the known and new mHAgs involved in GvHD and GvL effects.
167

La terapia demetilante con 5-azacitidina nelle sindromi mielodisplastiche: esperienza clinica del Nostro Istituto e correlazione con i dati biologici / Demethylating therapy with 5-azacitidine in myelodysplastic syndromes: clinical experience of our Institute and relationship with molecular response

Clissa, Cristina <1979> 06 June 2013 (has links)
Sulla base delle evidenze della letteratura (Fenaux, 2009; Lyons, JCO 2009), a partire da Settembre 2004 nel Nostro Istituto sono stati trattati 57 pazienti affetti da Sindrome Mielodisplastica (MDS) mediante terapia demetilante con 5-Azacitidina. Sono stati utilizzati differenti regimi terapeutici a seconda della classe di rischio IPSS: i pazienti a rischio basso/intermedio-1 hanno ricevuto Azacitidina 75 mg/mq/die sottocute per 5 giorni/mese (schema 5) per 8 cicli; i pazienti a rischio alto/intermedio-2 hanno ricevuto Azacitidina 50 mg/mq/die sottocute per 10 giorni/mese (schema 5+2+5) o Azacitidina 75 mg/mq/die per 7 giorni/mese (schema 7) fino a perdita della risposta. Su una casistica totale di 57 pazienti (15 a rischio basso/int-1; 41 rischio alto/int-2), l’87.7% (50 pazienti) sono risultati valutabili. Tra questi le risposte osservate sono state del 68% (34 pazienti), di cui il 14% (7 pazienti) ha ottenuto una Remissione Completa (CR) ed il 54% (27 pazienti) ha ottenuto un Hematologic Improvement (HI). La valutazione della risposta è stata eseguita secondo i criteri dell’International Working Group 2006 (IWG, Cheeson 2006). Le principali tossicità osservate sono state rappresentate da reazioni cutanee locali nel sito d’iniezione, tossicità gastrointestinale (stipsi e/o diarrea), mielotossicità, neutropenia febbrile, sepsi (3 pazienti). Tra i pazienti trattati abbiamo osservato la presenza di risposta ematologica prolungata (≥ 20 mesi) in 10 pazienti (20% dei pazienti valutabili). Inoltre, grazie alla collaborazione con il Dipartimento di Anatomia Umana dell’Università di Bologna (Prof. L. Cocco, Dott.ssa M.Y. Follo), tutti i pazienti trattati sono stati valutati per i livelli di espressione genica e metilazione del gene della fosfolipasi PI-PLC-beta1. I dati biologici così ottenuti sono stati correlati con quelli clinici, evidenziando la presenza di una correlazione tra i livelli di espressione genica e mutilazione della PI-PLC-beta1 e la risposta alla terapia demetilante con 5-Azacitidina. / Based on the evidence of literature (Fenaux 2009; Lyons 2009), from September 2004, in our Institute, 57 patients (pts) with Myelodysplastic Syndrome were treated (MDS) with demethylating therapy. We used 4 different regimens depending on the class of IPSS risk: patients at risk low/int-1 received Azacitidine 75 mg/sqm/day subcutaneously for 5 days/month (AZA 5) for 8 cycles, patients at risk high/int-2 received Azacitidine 50 mg/sqm/day subcutaneously for 10 days/month (AZA 5-2-5) or Azacitidine 75 mg/sqm/day for 7 days/month (AZA 7) until loss of response. On a series total of 57 pts (15 lower risk; 41 higher risk), 87 .7% (50 pts) were evaluable. Among these, responses observed were 68% (34 pts): 14% (7 pts) achieved complete remission (CR) and 54% (27 pts) had a Hematologic Improvement (HI). The assessment of response was performed according to the criteria of the International Working Group 2006 (Cheeson 2006). The main toxicities observed were represented by local skin reactions at the injection site, gastrointestinal toxicity (constipation and/or diarrhea), myelotoxicity, febrile neutropenia, sepsis (3 pts). Among the patients we observed the presence of prolonged hematologic response (≥ 20 months) in 10 pts (20% of evaluable patients). In addition, thanks to the collaboration with the Department of Human Anatomy, University of Bologna (Prof. L. Cocco, Dr. Follo MY), all patients were evaluated for levels of gene expression and gene methylation of phospholipase PI PLC- ß 1. The biological data obtained were correlated with clinical, highlighting the presence of a correlation between the levels of gene expression and mutilation of PI-PLC-ß1 and response to therapy with demethylating 5-Azacitidine.
168

SMO inhibitor specifically targets the Hedgehog Pathway and reverts the drug-resistance of Leukemic Stem Cells

Guadagnuolo, Viviana <1982> 06 June 2013 (has links)
Abnormal Hedgehog signaling is associated with human malignancies. Smo, a key player of that signaling, is the most suitable target to inhibit this pathway. To this aim several molecules, antagonists of Smo, have been synthesized, and some of them have started the phase I in clinical trials. Our hospital participated to one of these studies which investigated the oral administration of a new selective inhibitor of Smo (SMOi). To evaluate ex vivo SMOi efficacy and to identify new potential clinical biomarkers of responsiveness, we separated bone marrow CD34+ cells from 5 acute myeloid leukemia (AML), 1 myelofibrosis (MF), 2 blastic phases chronic myeloid leukemia (CML) patients treated with SMOi by immunomagnetic separation, and we analysed their gene expression profile using Affimetrix HG-U133 Plus 2.0 platform. This analysis, showed differential expression after 28 days start of therapy (p-value ≤ 0.05) of 1,197 genes in CML patients and 589 genes in AML patients. This differential expression is related to Hedgehog pathway with a p-value = 0.003 in CML patients and with a p-value = 0.0002 in AML patients, suggesting that SMOi targets specifically this pathway. Among the genes differentially expressed we observed strong up-regulation of Gas1 and Kif27 genes, which may work as biomarkers of responsiveness of SMOi treatment in CML CD34+ cells whereas Hedgehog target genes (such as Smo, Gli1, Gli2, Gli3), Bcl2 and Abca2 were down-regulated, in both AML and CML CD34+ cells. It has been reported that Bcl-2 expression could be correlated with cancer therapy resistance and that Hedgehog signaling modulate ATP-binding (ABC) cassette transporters, whose expression has been correlated with chemoresistance. Moreover we confirmed that in vitro SMOi treatment targets Hedgehog pathway, down-regulate ABC transporters, Abcg2 and Abcb1 genes, and in combination with tyrosine kinase inhibitors (TKIs) could revert the chemoresistance mechanism in K562 TKIs-resistant cell line.
169

Un estere misto degli acidi ialuronico, butirrico e retinoico è in grado di agire come rimodellante inverso della matrice cellulare sui fibroblasti cardiaci / Hyaluronan ester of butyric and retinoic acid acts as a reverse-remodeler of extracellular matrix patterning in cardiac fibroblasts

Cavallini, Claudia <1976> 29 May 2013 (has links)
Le cardiomiopatie che insorgono a seguito di infarto miocardico sono causa di elevata morbilità e mortalità dalle importanti ricadute cliniche, dovute alle patologie insorgenti a seguito dell’ischemia e della cicatrice post-infatuale. Il ventricolo sinistro danneggiato va incontro a un rimodellamento progressivo, con perdita di cardiomiociti e proliferazione dei fibroblasti, risultante in un’architettura e in una funzionalità dell’organo distorta. I fibroblasti cardiaci sono i principali responsabili della fibrosi, il processo di cicatrizzazione caratterizzato da un’eccessiva deposizione di matrice extracellulare (ECM). Negli ultimi anni gli sforzi del nostro laboratorio sono stati volti a cercare di risolvere questo problema, attraverso l’uso di una molecola da noi sintetizzata, un estere misto degli acidi butirrico, retinoico e ialuronico, HBR, capace di commissionare le cellule staminali in senso cardio-vascolare. Studi in vivo mostrano come l’iniezione diretta di HBR in cuori di animali sottoposti a infarto sperimentale, sia in grado, tra le atre cose, di diminuire la fibrosi cardiaca. Sulla base di questa evidenza abbiamo cercato di capire come e se HBR agisse direttamente sui fibroblasti, indagando i meccanismi coinvolti nella riduzione della fibrosi in vivo.. In questa tesi abbiamo dimostrato come HBR abbia un’azione diretta su fibroblasti, inibendone la proliferazione, senza effetti citotossici. Inoltre HBR induce una significativa riduzione della deposizione di collagene.. HBR agisce sull’espressione genica e sulla sintesi proteica, sopprimendo la trascrizione dei geni del collagene, così come dell’a-sma, inibendo la trasizione fibroblasti-miofibroblasti, e promuovendo la vasculogenesi (attraverso VEGF), la chemoattrazione di cellule staminali (attraverso SDF) e un’attività antifibrotica (inibendo CTGF). HBR sembra modulare l’espressione genica agendo direttamente sulle HDAC, probabilmente grazie alla subunità BU. L’abilità di HBR di ridurre la fibrosi post-infartuale, come dimostrato dai nostri studi in vivo ed in vitro, apre la strada a importanti prospettive terapeutiche. / Myocardial dysfunction resulting from myocardial infarction is a widespread and important cause of morbidity and mortality. Due to scar- and ischemia-related postinfarction events, clinical manifestations are enormous and heterogeneous. Damaged left ventricle undergoes progressive ‘‘remodelling’’, with myocyte slippage and fibroblast proliferation, resulting in distorted organ architecture and function. Cardiac fibroblasts (CFs) are principally responsible for fibrosis; a scarring process characterized by excessive deposition of extra cellular matrix (ECM) proteins. In the past year we’ve already explored new solution to this growing problem, and our effort focused on a chemical compound, HBR, able to improve the cardiac commitment of stem cells. HBR is a glycoconjugate of hyaluronan, butirric and retinoic acid. Our in vivo study showed that direct injection of HBR on infarcted heart is able, amongst other things, to reduce cardiac fibrosis. On the basis of this evidence, we did a step back, trying to discover pathways and cellular mechanisms involved in this reduced fibrosis in vivo, focusing on in vitro study on rat fibroblasts. Here we demonstrate that HBR was able to act directly on CFs limiting their activation and their biological activities. HBR acted on cell number, arresting cell proliferation, without any cytotoxic effects. Regarding ECM deposition, HBR lead a significative reduction of collagen deposition mediated by CFs. HBR acted on gene expression and protein synthesis, suppressing collagen gene expression, as well as myofibroblast differentiation through α-sma inhibition and promoting vasculogenesis (up regulation of VEGF), stem cell recruitment (up regulation of SDF) and had antifibrotic activity (downregulation of CTGF). HBR seems to modulate gene expression acting directly on HDAC proteins, effect probably due to BU moiety. The ability of our HBR to reduce fibrosis after MI, as demonstrated in our in vivo and in vitro study, opens an interesting therapeutic prospective.
170

Caratterizzazione citogenetico-molecolare alla diagnosi di pazienti con leucemia mieloide cronica in fase cronica trattati con inibitori delle tirosinchinasi: ruolo prognostico. / Cytogenetic and molecular characterization in newly diagnosed chronic-phase chronic myeloid leukemia patients treated with tirosine kinase inhibitors: prognostic role.

Luatti, Simona <1974> 06 June 2013 (has links)
L’applicazione della citogenetica convenzionale e molecolare può identificare: Ph-negatività, traslocazioni t(9;22) varianti e alterazioni citogenetiche addizionali (ACA) al cromsoma Ph in pazienti con LMC alla diagnosi. Prima dell’introduzione della terapia con Imatinib, esse mostravano un impatto prognostico negativo o non chiaro. Nel nostro studio, 6 casi di LMC Ph- erano trattati con Imatinib. La FISH identificava 4 casi con riarrangiamento BCR/ABL sul der(9q), 1 sul der(22q) e 1 su entrambi i derivativi. Quattro pazienti (66,7%) raggiungevano la RCgC, 2 fallivano il trattamento e 1 sottoposto a TMO. A causa dello scarso numero di casi, non era possibile nessuna correlazione con la prognosi. Nell’ambito di studi prospettici multicentrici del GIMEMA-WP, abbiamo valutato: traslocazioni varianti e ACA. Dei 559 pazienti arruolati, 30(5%) mostravano traslocazioni varianti, 24 valutabili in FISH: 18(75%) mostravano meccanismo 1-step, 4(16,7%) meccanismo 2-step e 2(8,3%) meccanismo complesso. Abbiamo confermato che le varianti non influenzano la risposta e la sopravvivenza dei pazienti trattati con Imatinib. Dei 378 pazienti valutabili alla diagnosi con citogenetica convenzionale, 21(5,6%) mostravano ACA: 9(43%) avevano la perdita del cromosoma Y, 3(14%) trisomia 8, 2(10%) trisomia 19, 6(28%) altre singole anomalie e 1 cariotipo complesso. La presenza di ACA influenzava la risposta: le RCgC e RMolM erano significativamente più basse rispetto al gruppo senza ACA e le curve di sopravvivenza EFS e FFS non erano significativamente diverse. Le curve di PFS e OS erano sovrapponibili nei due gruppi, per il basso numero di eventi avversi oppure perché alcuni raggiungevano la risposta con TKI di seconda generazione. Le anomalie “major route” mostravano decorso clinico peggiore, ma non è stato possibile determinare l’impatto prognostico in relazione al tipo di alterazione. Pertanto, le ACAs alla diagnosi rivestono un ruolo negativo nella prognosi dei pazienti trattati con Imatinib, che quindi rappresentano una categoria più a rischio per la risposta. / At diagnosis in chronic myeloid leukemia (CML) patients, conventional cytogenetics and FISH analysis can identify: Ph- CML cases, variant t(9;22) translocations and additional chromosomal abnormalities (ACAs) in Ph-positive clone. Before the introduction of the Imatinib therapy, these characteristics showed a negative or not clear prognostic role. We analysed 6 Ph- cases treated with Imatinib. FISH analysis showed 4 cases with BCR/ABL rearrangement on der(9q), 1 on der(22q) and 1 on both derivatives chromosomes. Four patients (66,7%) reached CCgR, 2 failed treatment and 1 died after stem cell transplantation. Beacause of small of number of cases, we cannot stated that Ph-masked cases have a worse prognosis. Within the clinical trial of GIMEMA WP, we have analysed variant t(9;22) translocations and ACAs. Five-hundred-fifty-nine patients were enrolled; 30(5%) had variant translocations of which 24 could be evaluated by FISH: 18(75%) showed 1-step mechanism, 4(16,7%) 2-step mechanism and 2(8,3%) complex mechanism. We observed that variant translocations didn’t influence the responses and the outcome in patients treated with Imatinib. At diagnosis, 378 patients were evaluable by cytogenetics. Twenty-one (5,6%) showed ACAs: 9 (43%) had loss of Y chromosome, 3(14%) trisomy 8, 2(10%) trisomy 19, 6(28%) other isolated abnormalities and 1(15%) complex karyotype. We reported that the presence of ACAs influenced the responses: the CCgR and MMolR were significantly lower compared with those of the group without ACAs, but EFS and FFS were not significantly different. PFS and OS curves were overlapped, because of the low number of negative events or because some patients reached response with second generation TKI treatment. Cases with “major route” abnormalities showed worse outcome, but we cannot established the impact related to the kind of abnormality. However, ACAs at diagnosis had a negative role on the response to the therapy in CML patients, which constitute a “warning” category for Imatinib treatment.

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