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STARR vs internal delorme for obstructed defecation: a prospective randomized trial.
No full textTransanal rectal resection with two circular staplers (STARR) and transanal mucosectomy (endorectal proctopexy or Internal Delorme) are two effective surgical approaches to severe obstructed defecation syndrome (ODS)associated to rectocele and rectal intussusception. Thirteen cinsecutive patients with ODS (average age 56.6 years) underwent surgery at Luigi Sacco University Hospital of Milan between October 2009 and February 2011. After routinely preoperative diagnostic work-up, patients were randomized to STARR (n=7) or Delorme procedure (n=6). All patients were submitted to three questionnaires: SF-36, ODS score and Wexner Continence Score before and after surgery (3 months, 1 and 4 years). All data and post operative complaints were recorded and collected by an independent investigator. All variables related to ODS symptoms have improved with both surgical techniques at 3 months, 1 year and 4 years (p<0,05). No major complication occurred. The overall short-term minor complications rate was 3/7 in the STARR group and 3/6 in the Internal Delorme group. Our study confirms the safety and the efficacy of the surgical approach with STARR or with Internal Delorme procedure in selected patients with ODS. Global health and psychological well being at 3 months, 1 year and 4 years after surgery are similar for both techniques
Enzyme promiscuity in amino acid oxidases: a tool for sustainable processes.
No full textEnzymatic promiscuity is the ability of enzymes to catalyze additional reactions different from those for which they have evolved. This phenomenon plays a key role in the divergent evolution of novel enzymes. Amino acid oxidases (AAOs) are a group of FAD containing enzymes that catalyze the oxidative deamination of amino acids. AAOs evolved to fulfill very different physiological roles, by reshaping of their functional and structural features. Thus these enzymes represent an ideal model to understand the mechanisms that originated molecular biodiversity in modern enzyme families. In addition, their strict enantioselectivity renders AAOs interesting biocatalysts for the production of optically pure amino acids, valuable compounds widely used in the pharmaceutical and food industries. Through extensive literature and database search we identified two novel L-amino acid oxidases (LAAOs).
Detailed structural and functional characterization showed that the first one, the aminoacetone oxidase from S. oligofermentans (SoAAO), is not a canonical LAAO, since it does no possess the typical features of these enzymes, and has only a low promiscuous activity on L-amino acids. Its preferred substrate is aminoacetone that is converted to 2,5-dimethylpyrazine. Thus we propose that SoAAO could act as a scavenger of aminoacetone (a prooxidant metabolite), protecting the cell from oxidative damage.
The second one, L-amino acid deaminase from P. myxofaciens (PmaLAAD), resembles more closely the typical LAAOs: it is a membrane associated protein active on large hydrophobic L-amino acids. PmaLAAD does not use molecular oxygen, but a cytochrome b-like protein, as a direct electron acceptor. We propose that PmaLAAD is involved in catabolic utilization of L-amino acids to fuel the electron-transfer chain of Proteus membranes.
Comparison of the 3D structure of the two proteins with other LAAOs reveals that SoAAO diverged very early from this group of flavoenzymes, originating a novel structural group, while PmaLAAD has a clear evolutionary link with LAAOs.
In conclusion, the characterization of two novel microbial LAAOs allowed us to define their structure/function relationships, to clarify their physiological role and to obtain new insights on the underlying mechanisms of the molecular evolution of AAOs
Structural studies of active pharmaceutical ingredients: polymorphism and solid-state reactivity.
No full textPolymorphism, the ability of a substance to crystallize in two or more different structures, is a fundamental issue in the Pharmaceutical Industry because API’s can indeed afford multiple solid phases. As different crystalline forms can have different properties, polymorphic identity can have influence on processability, handling, formulability and also the physico-chemical and pharmacological properties of the finished drug product. Characterizing the various crystalline forms of API’s is therefore crucial.
Structural studies can help interpreting the origin, and the consequences, of polymorphism, yielding important information on phase transitions or thermal and chemical stability. As the classical technique for structural analysis, single crystal X-ray diffraction, is not always applicable to solid forms of API’s, structure solution from powder diffraction data is an ideal solution.
Here, structure determination from laboratory X-ray powder diffraction (XRPD) data is successfully carried out on different API’s, illustrating the potential and usefulness of the technique. Three different species are studied (bupropion hydrohalide salts, nortriptyline hydrochloride and ibuprofen lysine salt), exploring different aspects (conformational and packing polymorphism, solvation/desolvation processes, thermodynamic relations and thermally-induced phase transitions).
Finally, a new approach to Quantitative Phase Analysis, implemented in a publicly available software, has been tested on an API, particularly relevant when accessibility to the complete structural model is hampered by the complexity of the molecular/crystal form, not amenable to ab-initio XRPD characterization
Reaction-diffusion models on a network: stochastic and deterministic pattern formation.
No full textThis thesis deals with the study of pattern formation on complex networks, a topic of paramount importance in different fields of broad applied and fundamental interest. Starting from a prototypical reaction-diffusion model, two main directions of investigation have been explored: on the one side, we have examined the system in its deterministic limit. Partial differential equations hence govern the evolution of the concentrations of the interacting species. In the second part of the thesis, we have conversely adopted a stochastic viewpoint to the scrutinized problem. Both in the deterministic and in the stochastic settings, the species are assumed to populate a complex graph, which provide the spatial backbone to the inspected model. Diffusion is allowed between neighbouring nodes, as designated by the associated adjacency matrix.
According to the deterministic formulation, a small perturbation of a homogeneous fixed point can spontaneously amplify in a reaction-diffusion system, as follow a symmetry breaking instability and eventually yield asymptotically stable non homogeneous patterns. These are the Turing patterns. Travelling waves can also develop as follows an analogous dynamical instability. In this Thesis we have considered the peculiar setting where the spatial support is a directed network. Due to the structure of the network Laplacian, the dispersion relation has both real and imaginary parts, at variance with the conventional case for a symmetric network. The homogeneous fixed point of the system can turn unstable because of the topology of the hosting network. This observation motivates the introduction of a new class of instabilities, termed topology driven, which cannot be induced on undirected graphs. A linear stability calculation enables one to analytically trace the boundaries of the instabilities in the relevant parameters plane. Numerical simulations show that the instability can lead to travelling waves, or quasi-stationary patterns, depending on the characteristics of the underlying graph. Another scenario where topology matters is that of multi-layered networks, also known as multiplex networks. We have shown in this Thesis that the emergence of self-organized patterns on a multiplex can be instigated by a constructive interference between layers. It can be in fact proven that patterns can emerge for a reaction-diffusion system defined on a multiplex, also when the Turing-like instability is prevented to occur on each single layer taken separately. In other cases inter-layer diffusion can have a destructive influence on the process of pattern formation, as we will discuss in details in this Thesis work.
Beyond the deterministic scenario, single individual effects can also impact the process of pattern formation. Stochastic fluctuations, originating from finite size populations, can in fact significantly modify the mean-field predictions and drive the emergence of regular macroscopic patterns, in time and space, outside the region of deterministic instability. In the second part of the Thesis we have studied the dynamics of stochastic reaction-diffusion models defined on a network. A formal approach to the problem has been developed which makes use of the Linear Noise Approximation (LNA) scheme. Simulations based on the Gillespie algorithm were performed to test the analytical results and analyzed via a generalized Fourier transform which is defined using the eigenvectors of the discrete graph Laplacian. Travelling waves as well as stationary patterns reminiscent of the Turing instability are shown to develop as mediated by the discreteness of the stochastic medium. As a final point we considered the case of a general stochastic reaction-diffusion system, where the activator is solely allowed to diffuse. Working under the LNA, we proved that stochastic Turing like pattern can develop, an observation which marks a striking difference with the conventional, customarily adopted, deterministic scenario
Analysis of the role of liprins protein in breast cancer cell invasion.
No full textThe metastatic process requires the ability of cancer cells to break the basement mem¬brane and migrate through a complex three-dimensional environment. The laboratory has recently identified the protein liprin-α1 as an important regulator of integrin me¬diated focal adhesion dynamics and cell motility in non-neuronal cells (Asperti et al., 2009, Asperti et al., 2010). Liprins are a family of cytosolic scaffold proteins including the liprin-α and liprin-β subfamilies based on sequence similarities (Serra Pagés et al., 1998). The human genome encodes four liprin-α (liprin-α1-4) and two liprin-β proteins (liprin-β1 and liprin-β2). Interestingly, the gene PPFIA1 for liprin-α1 is frequently am-plified in tumors. Moreover, the levels of expression of the liprin-α1 protein are often increased in human breast cancers (Astro et al., 2011). Functional analysis has revealed that liprin-α1 is specifically required for migration and invasion in vitro of highly invasi¬ve MDA-MB-231 human breast cancer cells. The analysis of lamellipodia dynamics has revealed a decrease of the stability of these protrusions in cells depleted of endogenous liprin-α1, which are defective in cell motility. Furthermore, liprin-α1 silencing causes a reduction of tumor cell invasion through Matrigel. The examination of the invasive po¬tential has demonstrated that liprin-α1 is important also for the degradation of the extra¬cellular matrix (ECM) (Astro et al., 2011). Starting from these observations, the first aim of my project has been to investigate the function of liprin-α1 in vivo. I have generated MDA-MB-231-derived cell lines with either stable overexpression or stable depletion of liprin-α1, and I have used these cells for injection or transplantation in mice, to determine their invasive potential. The characterization of these cell lines in vitro has confirmed that liprin-α1 overexpression causes an increase of both cell migration on FN and invasion through Matrigel, by promoting the stability of the lamellipodia. On the other hand, li¬prin-α1-depleted cells have reduced ability to both migrate and invade in vitro. However, all the cell lines with altered liprin-α1 levels have shown similar proliferation rates and viability compared to the control MDA-MB-231 cells. To investigate the involvement of liprin-α1 in invasion in vivo, experimental metastasis assays and spontaneous metastasis assays were performed. In both assays, the formation of lung metastases by the modified and control breast cancer cell lines has been evaluated. The results indicated that liprin-α1 overexpression did not affect lung colonization. Considering the high invasive ability of MDA-MB-231 wild type cells, increase in lung colonization by liprin-α1 overexpression may be irrelevant in vivo. On the contrary, injection of liprin-α1-depleted cells resulted in the reduction of the formation of lung metastases compared to control cells. This is the first evidence that liprin-α1 is not involved in primary tumor growth, while it is important for tumor cell invasion.
Being a scaffold protein, liprin-α1 is unlikely to act alone as a regulator of tumor cell invasion. Previous studies have described the interaction between liprin-α1 and liprin-β1 (Serra-Pages et al., 1998), and have suggested a possible role of liprin-β2 in migration and invasion (von Thun et al., 2012). However, the available data on the functions of li¬prin-β proteins and their relationship with liprin-α1 are not exhaustive. As the second aim of my PhD, I have addressed the biochemical interaction of liprin-α1 with either liprin-β1 or liprin-β2, and I have tried to elucidate the role of the two proteins in cell motility and invasion. While liprin-α1 interacts with liprin-β1, it does not interact with liprin-β2. This is the first evidence of the different ability of the two liprin-β proteins to interact with liprin−α1. The biochemical analysis has shown that the interaction between liprin-α1 and liprin-β1 occurs via the C-terminus of liprin-α1, and that two of the three SAM domains of liprin-α1 are sufficient to mediate this interaction.
The study of the subcellular localization has indicated that liprin-β1 colocalizes with liprin-α1 at the cell edge, whereas liprin-β2 partially colocalizes with cortactin-positive invadopodia. Functional analysis has shown that liprin-β1 silencing did not affect cell invasion through matrigel, whereas liprin-β2 silencing led to an increase of cell invasion, and enhanced ECM degradation, supporting the hypothesis of the different role of this protein in regulating the function of invadopodia with respect to liprin-α1 and liprin-β1. Analysis of the involvement of liprin-β1 and liprin-β2 in cell migration underlined the different effects of the two proteins. As previously observed for liprin-α1 (Astro et al, 2011), silencing of liprin-β1 led to a decrease of the speed of the cells in random migra¬tion assays. On the contrary, liprin-β2 silencing did not significantly affect cell motility. These data support the hypothesis of a cooperation between liprin-α1 and liprin-β1 in regulating cell motility, while they indicate that liprin-β2 does not have a relevant role in this process.
Altogether the work presented in my thesis sustains a key role of liprin-α1 as a positive regulator of the invasive apparatus of tumour cells in vivo, and has highlighted for the first time first time distinct roles of liprin-β1 and liprin-β2 in tumor cell motility
Hemp hurds biorefining for chemicals productions. Chemical characterization, organosolv fractionation and enzymatic depredation for sugars exploitation
No full textLignocellulosic biomass has been highlighted to be a sustainable and renewable feedstock for fossil source replacement. As in the petroleum refinery, the challenges are in making the cellulose fraction accessible to enzymes during enzymatic hydrolysis and maximizing the utilization of all the constituents within the feedstock. In a biorefinery facility the fermentation of the saccharidic fraction to liquid fuels or chemicals provide the gross value, whereas the valorization of the others constituents help to make the process economically viable. In this work the effective fractionation of hemp hurds (HH) into its three main components, cellulose, hemicellulose, and lignin, has been obtained by means of an organosolv pretreatment step followed by enzymatic hydrolysis of the pretreated HH. The effect of different process variables and the kinetic of enzymatic hydrolysis have been studied; the two steps were optimized to yield the highest amounts of fermentable monomeric xylose (from hemicellulose, C5) and glucose (from cellulose, C6). The aptness of C5 and C6 streams has been evaluated, in a fermentation process, by producing butanol and lactic acid, two of the most valuable platform chemicals for biorefinery. In particular, 42 g of polymer-grade lactic acid has been obtained from 100 g of raw HH. These results can be considered promising for HH valorization through the biorefinery concept
Disturbo bipolare e asenapina: efficacia clinica e incidenza di effetti collaterali.
No full textThe study aims to evaluate the therapeutic response of Bipolar Disorder in the manic phase introduction FGA, SGA and mood stabilizer (1st Part) and the use of Asenapine in clinical practice in the treatment of Bipolar Disorder by detecting any side effects metabolic, endocrinological and elettrocardiographic (2nd Part).
In the 1st Part, in patients with Bipolar Disorder type I some psychometric scales (YMRS, CGI-BD, MADRS, FAST) were administered in five consecutive visits over three months.
In 2nd Part at baseline and 3 months of treatment with Asenapine it was recorded metabolic parameters, electrocardiograms, vital signs and clinical data of patients.
The study confirmed that in patients with Bipolar Disorder type I in the manic phase the manic symptoms (YMRS), depressive symptoms (MADRS), the clinical conditions (CGI-BP) and global functioning (FAST) improve within 12 weeks from the introduction of antipsychotics or mood stabilizers regardless of intrinsic and extrinsic factors.
These data are confirmed by both the experimental center of Varese and OSTER study (which ad respectively 8 and 192 patients that completed the protocol).
In 2nd Part there are 26 enrolled patients, 17 women and 9 men, mean age 44 ± 13,8 years, we obtained incomplete data for an in-depth statistical analysis but this sample allowed us to observe that only 26,9% of patients were affected by Bipolar Disorder type I. Most of the requirements was in fact off label, mostly in patients with personality disorder, but also schizoaffective disorder and psychosis, with variable dosages from 5 to 20 mg/die.
There were no statistically significant metabolic side effects
Perfusione meccanica ipotermica nel trapianto di rene da donatore marginale: follow up a breve e lungo termine.
No full textmissin
Tempo razionale e tempo irrazionale nella generazione dei flussi di coscienza”. Un’indagine tematica sulle funzionalità della memoria come elemento costitutivo dell’identità psichica
No full textL’analisi del concetto di tempo ha prodotto un enorme numero di riflessioni e di teorie, delineando posizioni problematiche. Un grande problema, forse di fatto insolubile, è legato al fatto che il tempo è un oggetto di considerazione e, contemporaneamente, va a coincidere con lo stesso soggetto considerante.
Il tempo presente, poi, ha da sempre, diverse facce. Talvolta nette e precise; talaltra sfumate e soffuse. Facce diverse, eppure tanto interconnesse che quasi trenta secoli di indagine filosofica e quattro di indagine scientifica non sono riusciti a risolverle.
Il tempo si può esperire attraverso un continuum misurabile ad una sola dimensione ma, contemporaneamente, il tempo risulta composto da un’estensione passata e di un’estensione futura, il cui punto di confine è, di per sé, privo di estensione. Eppure è l’unico che riusciamo a percepire poiché è il tempo del soggetto considerante.
Ancora una volta, quindi, il tempo rimane avvolto da un mistero ultimo e appare, almeno nella sua totalità, incomprensibile.
Qualcosa, però, sappiamo con certezza: il tempo non è un accidente della vita bensì ne è l’essenza, l’elemento fondante, impalpabile, inspiegabile, incomprensibile, che tutto impregna e pervade.
Dunque, se il tempo non è soltanto un fattore esterno dell’esistenza umana, allora la memoria, generata dal suo fluire, è qualcosa di più della semplice reminiscenza.
Nel percorso tematico articolato in questa tesi abbiamo cercato di esaminare come il tempo, nelle sue due dimensioni, quella razionale e quella irrazionale, sia proprio un elemento costitutivo dell’esperienza umana e come quest’ultima contribuisca alla formazione della coscienza della persona e della sua identità psichica, formata da un conscio e da un inconscio. Non è, infatti, paradossale affermare che soltanto gli esseri coscienti, intesi come coloro che hanno sviluppato una coscienza del senso, possono possedere anche un inconscio.
Le questioni urgenti dello sviluppo della scienza e il diffondersi della tecnocrazia che, da ormai quasi un secolo, stanno imperversando nelle nostre terre occidentali, hanno fatto sì che problematiche come il tempo, la vita, lo spirito, il divino e le tematiche metafisiche più in generale, venissero accantonate per dare spazio ad argomenti più concreti e a riflessioni di stampo epistemologico. In questo modo, però, l’uomo è rimasto, nei confronti del proprio Essere, sprovvisto di risposte soddisfacenti che ha rimpiazzato con l’abuso di strumenti tecnologici attraverso i quali ha sperato di appagare corpo e anima.
Purtroppo, invece, le tematiche metafisiche trattano delle questioni supreme dell’uomo, soprattutto quando si trova di fronte alla sfida del significato stesso dell’essere umano, reale e vivo, e ancora, quando si trova di fronte al problema dell’esistere e della sopravvivenza.
Gli sviluppi tecnologici introdotti dall’avvento dei computer e della realtà virtuale hanno aperto, in questi ultimi decenni, una feconda stagione di ricerche, dando origine a nuove ipotesi che hanno coinvolto la filosofia del linguaggio e le psicologie cognitiviste con l’intento di rendere più comprensibili alcuni fenomeni dell’attività percettiva e noetica dell’uomo. Da queste nuove ipotesi e da questi nuovi strumenti tecnologici si sono, inoltre, generate alcune terre di confine ancora da esplorare.
Una di queste è il territorio delle neuroscienze che sconfina nella medicina da un lato e nella psicologia dall’altro, utilizzando a piene mani il potenziale tecnologico offerto dalle nuove scoperte informatiche e scientifiche.
La relazione tra spirito e materia trova, infatti, oggi come nell’antichità, ancora diversi nodi da sciogliere e, nonostante l’attuale proliferazione di modelli epistemologici, la filosofia contemporanea fatica a individuare i confini del proprio indagare.
La riflessione di Bergson, che abbiamo utilizzato come palinsesto del nostro impianto teoretico, si ripresenta oggi più attuale che mai e potrebbe fornirci un modello di pensiero che possa essere utilizzato per indagare filosoficamente questa terra di confine chiamata neuroscienza poiché Bergson sviluppa una filosofia della durata interiore e della percezione pura muovendo da un interesse specifico per i fondamenti della fisica e della medicina; approderà all’idea straordinaria della memoria come ambito privilegiato della coscienza del sé che trova il suo fondamento nella concezione della natura dinamica dell’io e della realtà stessa.
La memoria, infatti, assume, in questa prospettiva, il valore di coscienza indivisa della propria durata, del proprio mutare e anche coscienza immediata del divenire delle cose. Senza memoria, dunque, non ci potrebbe essere nemmeno intuizione della durata, cioè dell’esistenza e dello scorrere della vita psichica.
L’uomo, dunque, è l’insieme delle emozioni, delle sensazioni, delle esperienze che ha vissuto, amalgamate sapientemente dalla memoria in modo che, nella coscienza, l’Io non possa ravvisare una distinzione del sé dal proprio vissuto.
Non vi sono dubbi, allora, sul fatto che solo grazie alla memoria e al ricordo la coscienza è in grado di organizzare le esperienze per farne narrazione; per esse, in qualche modo, creiamo una dimensione aggiuntiva che noi chiamiamo “tempo” ma che non ha durata in quanto si tratta di un semplice allineamento logico-deduttivo allineato con lo spazio (ciò che è accaduto prima, ciò che è accaduto dopo). Semplice giustapposizione.
Riassumendo, quindi, il tempo della coscienza del sé, avvero la durata reale, è molteplicità qualitativa di stati irrazionali che si compenetrano; successione senza giustapposizione; ma poiché dove c’è coscienza di qualcosa c’è anche memoria (quindi il sorgere di un prima e di un dopo) la durata reale è l’insieme dell’intensità dell’esperienza immediata percepita dalla coscienza che penetra nel flusso razionale del tempo.
Da qui è facilmente comprensibile come sia la dimensione irrazionale che la dimensione razionale del tempo siano indispensabili affinché l’uomo possa generare un flusso coscienziale che gli permetta di distinguere se stesso dall’alterità e lo renda creatura unica e irripetibile.
Quanto detto sino a ora ci permette di formulare un’ipotesi circa la struttura della coscienza. Il tempo esiste solo nel momento in cui percepiamo la nostra durata interiore; diversamente, come nel paziente psicotico o nel nevrotico, in cui il rapporto tra Io e coscienza è alterato dalla malattia, il tempo assume valori e misure differenti; non necessariamente più o meno attinenti al reale poiché per il paziente psicotico, o per il nevrotico, il reale corrisponde a ciò che percepisce il suo Io ed è, semplicemente, di qualità differente.
Lo stesso può essere osservato per la formazione del ricordo. Se non può esservi durata senza memoria, allora il problema della formazione del ricordo deve essere analizzato con la massima profondità possibile perché solo così si potrà tentare di formulare una risposta alla questione della realtà e della natura del tempo al di fuori della coscienza.
Da qui deriva che la memoria non può essere ridotta alla sola conservazione automatica del passato. Essa non può che derivare da una trasformazione qualitativa sia della formazione del ricordo che dell’evocazione del ricordo stesso. Insomma, perché ci sia coscienza, dunque memoria, è necessario che il dato percettivo sia sottoposto a un cambiamento strutturale e questa necessaria trasformazione si realizza proprio attraverso la durata, ovvero il tempo della coscienza.
Se la memoria è parzialmente conservazione del passato, questo passato conservato può essere reso presente solo grazie alla tensione del tempo della coscienza ed è proprio la coscienza, dunque, a illuminare, in ogni momento, quell’immediata parte di passato che, proteso sul futuro, lavora per realizzarlo e trasformare in ente ciò che è ancora niente.
The issues about development of science and the spread of technocracy that, for almost a century, are raging in our western lands, have allowed that issues such as the time, life, spirit or, more generally, the metaphysical topics, they were set aside to give way to more concrete topics and epistemological reflections.
In this way, however, the man was, in respect of its being, without a satisfactory response it has replaced with the abuse of technological tools by which he hoped to satisfy body and soul.
Unfortunately, however, the metaphysical issues concern the supreme question about man, especially when he is faced with the challenge of the very meaning of being human, real and alive, and yet, when he is faced with the problem of existence and survival.
In reasoning we sought, we examine how time in its two dimensions, is a constitutive element of human experience and how it contribute to the formation of the conscience of the person and of his psychic identity, composed of a conscious and an unconscious
Technological developments introduced by the coming of computers and virtual reality have opened in recent years, a rich season of research, giving rise to new theories; from these new hypotheses and from these new technological tools have also generated some border lands yet to be explored. One of these is the area of neuroscience.
The Bersgson’s reflection, which we used as a palimpsest of our theoretical foundation, persists today and could provide a model thought that can be used to investigate philosophically this borderland called neuroscience because Bergson develops a philosophy of inner life and pure perception moving from a focus on the fundamentals of physics and medicin
Human tumor retrovirus-host-interaction: role of CIITA in the functional inhibition of HTLV-1 Tax-1 oncogenic protein.
No full textHuman T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many evidences have shown that constitutive activation of NF-κB pathway by Tax-1 is crucial for T-cell transformation. Previous results demonstrated that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transcription function of the viral transactivator Tax-1.
Here we show that CIITA suppresses also Tax-1-mediated activation of the NF-κB pathway.
CIITA interacts with and retains Tax-1 in the detergent unsoluble cell fraction (cytoplasmic debris) and inhibits Tax-1-dependent nuclear translocation of RelA. Moreover, the overexpression of CIITA does not affect Tax-1 interaction with both RelA and IKKγ.
Nevertheless, the enzymatic activity of IKK kinase promoted by Tax-1 is impaired in the presence of CIITA. CIITA acts by suppressing at least the canonical NF-κB pathway, in that it also inhibits the activation of NF-κB by Tax-2, which is known to activate NF-κB through the canonical but not the non-canonical pathway. Overall, our results indicate that CIITA, beside acting as viral restriction factor against HTLV-1 infection, might counteract Tax-1 transforming activity. Thus, assessing the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential