Farmaci biosimilari e loro utilizzo nella pratica clinica

Grazie all'estinzione della copertura brevettuale di alcuni dei farmaci biotecnologici in commercio, si è aperto un nuovo scenario: quello dei farmaci biosimilari. Essi non possono essere definiti copie esatte del farmaco biologico di riferimento, bensì la loro caratteristica è quella di essere simili, ma non identici rispetto all'originatore. Questa sottile differenza è fondamentale per la loro caratterizzazione: si tratta infatti di molecole uniche nel loro genere che in definitiva non possono essere considerate come la “versione generica” del corrispettivo farmaco biologico. Essi si distinguono dai farmaci generici bioequivalenti sotto molteplici aspetti. Ciò è conseguenza della loro complessità strutturale e del processo di produzione sfruttato per la loro messa a punto. Nell'ambito dei farmaci biotecnologici e biosimili, struttura e fabbricazione sono tra loro strettamente interconnesse, tanto che anche piccole variazioni a livello del processo produttivo possono indurre grande variabilità nella struttura della proteina ricombinante ed avere conseguenze sulle caratteristiche biologiche e cliniche del prodotto finale in termini di sicurezza, potenza, efficacia ed immunogenicità. Per poter individuare anche la più piccola differenza tra farmaco biosimilare e farmaco di riferimento, riuscendo allo stesso tempo a garantire un loro sovrapponibile profilo di qualità, sicurezza ed efficacia, deve essere seguito un preciso e rigoroso iter: perché il prodotto sia approvato e immesso sul mercato, ne deve essere riconosciuta e dimostrata la comparabilità con il farmaco di riferimento sia dal punto di vista delle proprietà fisico-chimiche, sia rispetto a quanto emerge dagli studi preclinici e clinici condotti. Presentandosi il bisogno di regolamentare i diversi aspetti della produzione, sviluppo, dimostrazione di comparabilità, immunogenicità e farmacovigilanza, l'EMA ha elaborato per prima nel 2005 delle linee guida generali di riferimento e, a seguire, linee guida classe-specifiche in risposta alle particolari esigenze che col tempo si sono evidenziate per le diverse classi di farmaci. Il suo lavoro è servito da input e da stampo non solo per l'OMS (Organizzazione Mondiale della Sanità), ma anche per altri paesi come l'Australia, il Canada, il Giappone, la Corea e per la FDA (Food And Drug Administration), per disciplinare le varie dinamiche che ruotano attorno all'argomento. Inizialmente, al contrario di quanto ci si aspettasse, i biosimilari non hanno avuto un grande impatto sul mercato: l'insufficiente informazione e chiarezza in merito hanno fatto nascere dubbi e preoccupazioni nei clinici che spesso e volentieri continuano ad affidarsi ai farmaci biologici. L'aumento di prescrizioni e vendite dei medicinali biosimili, grazie al loro minor costo rispetto al farmaco di riferimento biotecnologico, permetterebbe di liberare importanti risorse economiche da reinvestire nella ricerca e nella produzione di farmaci innovativi e sarebbe vantaggioso sia per ridurre i costi della spesa farmaceutica, sia per consentire l'accesso alle cure di un numero ancora maggiore di pazienti. Senza dubbio la prospettiva è quella di andare incontro ad un futuro in cui questi farmaci finiranno per occupare sempre più ampio spazio nel panorama internazionale, man mano che l'esperienza clinica avanzerà e che il tempo riconoscerà loro effettiva sicurezza ed efficacia

C'è ancora un futuro per il servizio pubblico televisivo? Il caso italiano e un confronto con alcuni Paesi Europei.

Questo elaborato si propone di analizzare il mercato televisivo e in particolare il servizio pubblico televisivo offerto in Italia dalla RAI. C’è ancora un futuro per il servizio pubblico? Questo lavoro tenta di rispondere alla domanda, proponendo anche un paragone tra l’Italia e alcuni Paesi Europei (Regno Unito, Francia e Spagna). Il lavoro è suddiviso in quattro capitoli

La biblioteca en las redes sociales : Hacia un nuevo concepto en Unidades de Información

En la actualidad, la tecnología forma una parte importante en la vida de las personas y las unidades de información no están ajenas a este proceso. El desarrollo tecnológico ha revolucionado los distintos tipos de trabajos y el propio de una biblioteca ha tenido que modificarse en razón de los cambios en las demandas de los usuarios actuales, quienes plantean la exigencia de una respuesta en foco, rápida, directa y, sobre todo, relevante a las necesidades de información que posee. Todos estos factores han ido determinando la aparición de nuevos modelos de unidades de información: bibliotecas electrónicas, virtuales y digitales, la biblioteca en red, las bibliotecas híbridas, la biblioteca social y las bibliotecas móviles. Sin embargo, cada vez existen más unidades de información que hacen un uso de las redes sociales para distintos objetivos. Las bibliotecas visualizan a las redes sociales como una base o plataforma para el logro de comunicaciones rápidas, directas y eficaces con sus usuarios. Algunas de ellas las utilizan para difusión de los eventos y actividades que celebran, otras para comunicar distintas noticias, algunas para mostrar cómo son y qué hacen, brindarle a su comunidad enlaces de interés y, por sobre todas las cosas, para la comunicación con sus usuarios. En este sentido, esta ponencia busca diferenciar y caracterizar los distintos modelos de bibliotecas para culminar planteando las potencialidades de las nuevas bibliotecas en las redes sociales

Mental health treatment outcomes in a humanitarian emergency: a pilot model for the integration of mental health into primary care in Habilla, Darfur

BACKGROUND: There is no description of outcomes for patients receiving treatment for mental illnesses in humanitarian emergencies. MSF has developed a model for integration of mental health into primary care in a humanitarian emergency setting based on the capacity of community health workers, clinical officers and health counsellors under the supervision of a psychiatrist trainer. Our study aims to describe the characteristics of patients first attending mental health services and their outcomes on functionality after treatment. METHODS: A total of 114 patients received mental health care and 81 adult patients were evaluated with a simplified functionality assessment instrument at baseline, one month and 3 months after initiation of treatment. RESULTS: Most patients were diagnosed with epilepsy (47%) and psychosis (31%) and had never received treatment. In terms of follow up, 58% came for consultations at 1 month and 48% at 3 months. When comparing disability levels at baseline versus 1 month, mean disability score decreased from 9.1 (95%CI 8.1-10.2) to 7.1 (95%CI 5.9-8.2) p = 0.0001. At 1 month versus 3 months, mean score further decreased to 5.8 (95%CI 4.6-7.0) p < 0.0001. CONCLUSION: The findings suggest that there is potential to integrate mental health into primary care in humanitarian emergency contexts. Patients with severe mental illness and epilepsy are in particular need of mental health care. Different strategies for integration of mental health into primary care in humanitarian emergency settings need to be compared in terms of simplicity and feasibility

Suppressor of Cytokine Signaling-3 (SOCS-3) induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) expression in hepatic HepG2 cell line

The suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway activated by proinflammatory cytokines, including the tumor necrosis factor (TNF-\u3b1). SOCS3 is also implicated in hypertriglyceridemia associated to insulin resistance. Proprotein convertase subtilisin kexin type 9 (PCSK9) levels are frequently found to be positively correlated to insulin resistance and plasma very low density lipoprotein (VLDL) triglycerides concentrations. The present study aimed to investigate the possible role of TNF-\u3b1 and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. TNF-\u3b1 induced both SOCS3 and PCSK9 in a concentration-dependent manner. This effect was inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Retroviral overexpression of SOCS3 in HepG2 cells (HepG2SOCS3) strongly inhibited STAT3 phosphorylation and induced PCSK9 mRNA and protein, with no effect on its promoter activity and mRNA stability. Consistently, siRNA anti-SOCS3 reduced PCSK9 mRNA levels, whereas an opposite effect was observed with siRNA anti- STAT3. In addition, HepG2SOCS3 express higher mRNA levels of key enzymes involved in the de novo lipogenesis, such as fattyacid synthase, stearoyl-CoA desaturase (SCD)-1, and apoB. These responses were associated with a significant increase of SCD-1 protein, activation of sterol regulatory element-binding protein-1c (SREBP-1), accumulation of cellular triglycerides, and secretion of apoB. HepG2SOCS3 show lower phosphorylation levels of insulin receptor substrate 1 (IRS-1) Tyr896 and Akt Ser473 in response to insulin. Finally, insulin stimulation produced an additive effect with SOCS3 overexpression, further inducing PCSK9, SREBP-1, fatty acid synthase, and apoB mRNA. In conclusion, our data candidate PCSK9 as a gene involved in lipid metabolism regulated by proinflammatory cytokine TNF- in a SOCS3-dependent manner

El nuevo consumidor de información: ¿usuario o productor?: el re-planeamiento estratégico de las unidades de información

Durante esta última década las bibliotecas y los servicios de información documentales han realizado un enorme esfuerzo para poder seguir ocupando un papel destacado en La sociedad. Ellos, como organizaciones que gestionan información, han tenido que integrar em sus sistemas los cambios tecnológicos necesarios para adaptarse a los nuevos retos y estar lejos de desaparecer. En el último tiempo el término web 2.0 ha comenzado a utilizarse para nombrar a una nueva generación de servicios web que tienen como base una mayor implicación y colaboración de los usuarios web y la aplicación de una serie de tecnologías que permiten lamayor implicación de los mismos. Nuevos términos como booktubers, wikipedistas, ebookshan comenzado a aparecer siendo cada vez más comunes dentro del mundo de la información ya que permiten generar y compartir contenidos en una valía y forma diferenciada. Esta nueva realidad exige para las unidades de información la adopción de nuevas orientaciones estratégicas, el rediseño de los procesos técnicos y los flujos de información para encuadrar a las mismas dentro del universo de los servicios de información actuales. Hoy, el usuario es el protagonista y pasa de ser un mero espectador y consumidor de lo que se le ofrece a convertirse en creador y generador de nuevos contenidos y servicios. Así se plantea un nuevo desafío adicional para las unidades de información: el manejo del intercambio de información entre pares. El peer to peer, donde las bibliotecas, archivos y centros documentales podrían tomar un rol destacado siendo escenarios de la generación de nuevos conocimientos. ¿Serán las bibliotecas y las diferentes unidades de información capaces de canalizar estas nuevas inquietudes? ¿Podrán asumir un nuevo rol y convertirse en un vehículo de generación de una “nueva colección” por, para y entre los usuarios? Una reflexión, en estas páginas.Mesa 6: Gestión de unidades de informaciónDepartamento de Bibliotecologí

El nuevo consumidor de información: ¿usuario o productor?: el re-planeamiento estratégico de las unidades de información

Durante esta última década las bibliotecas y los servicios de información documentales han realizado un enorme esfuerzo para poder seguir ocupando un papel destacado en La sociedad. Ellos, como organizaciones que gestionan información, han tenido que integrar em sus sistemas los cambios tecnológicos necesarios para adaptarse a los nuevos retos y estar lejos de desaparecer. En el último tiempo el término web 2.0 ha comenzado a utilizarse para nombrar a una nueva generación de servicios web que tienen como base una mayor implicación y colaboración de los usuarios web y la aplicación de una serie de tecnologías que permiten lamayor implicación de los mismos. Nuevos términos como booktubers, wikipedistas, ebookshan comenzado a aparecer siendo cada vez más comunes dentro del mundo de la información ya que permiten generar y compartir contenidos en una valía y forma diferenciada. Esta nueva realidad exige para las unidades de información la adopción de nuevas orientaciones estratégicas, el rediseño de los procesos técnicos y los flujos de información para encuadrar a las mismas dentro del universo de los servicios de información actuales. Hoy, el usuario es el protagonista y pasa de ser un mero espectador y consumidor de lo que se le ofrece a convertirse en creador y generador de nuevos contenidos y servicios. Así se plantea un nuevo desafío adicional para las unidades de información: el manejo del intercambio de información entre pares. El peer to peer, donde las bibliotecas, archivos y centros documentales podrían tomar un rol destacado siendo escenarios de la generación de nuevos conocimientos. ¿Serán las bibliotecas y las diferentes unidades de información capaces de canalizar estas nuevas inquietudes? ¿Podrán asumir un nuevo rol y convertirse en un vehículo de generación de una “nueva colección” por, para y entre los usuarios? Una reflexión, en estas páginas.Mesa 6: Gestión de unidades de informaciónDepartamento de Bibliotecologí

Agronomic characterization of citrandarin fruits and seeds

In citrus cultivation, rootstocks are of fundamental importance and affect several characteristics of the variety used as canopy. Despite the great diversity within Citrus and related genera, the production of rootstocks in Brazil is restricted to a small number of varieties, making the citrus culture vulnerable to the appearance of phytosanitary problems. The aim of this study was to agronomically characterize fruits and seeds of seven citrandarins [Citrus sunki (Hayata) hort. ex Tanaka x Poncirus trifoliata cv. Rubidoux (L.) Raf.], obtained by controlled crossing. The orchard was installed in randomized blocks, with three replicates, in the municipality of Cordeirópolis, SP, where 20 fruits were collected in each replicate, obtained from free pollination of seven citrandarins, Swingle citrumelo and Rangpur lime. The following variables were evaluated: fruit mass, height, diameter, total number of seeds and percentage of viable seeds per fruit; number of embryos per seed, mass of one thousand seeds, number of seeds in 1.0 kg, final emergence rate, number of seedlings per seed, polyembryony rate, emergence speed index and seedling height at 60 days after sowing. For fruit size, the highest values were obtained for Swingle citrumelo. For number of embryos per seed, seedlings obtained through seed and polyembryony, citrandarin TSxPT 245 showed the highest values. Although citrandarin fruits had smaller size than fruits from commercial Rangpur lime and Swingle citrumelo rootstocks, characteristics related to seeds such as viability, polyembryony and emergence rate, were similar or superior, and can be considered potential new rootstocks for the production of citrus plants.In citrus cultivation, rootstocks are of fundamental importance and affect several characteristics of the variety used as canopy. Despite the great diversity within Citrus and related genera, the production of rootstocks in Brazil is restricted to a small number of varieties, making the citrus culture vulnerable to the appearance of phytosanitary problems. The aim of this study was to agronomically characterize fruits and seeds of seven citrandarins [Citrus sunki (Hayata) hort. ex Tanaka x Poncirus trifoliata cv. Rubidoux (L.) Raf.], obtained by controlled crossing. The orchard was installed in randomized blocks, with three replicates, in the municipality of Cordeirópolis, SP, where 20 fruits were collected in each replicate, obtained from free pollination of seven citrandarins, Swingle citrumelo and Rangpur lime. The following variables were evaluated: fruit mass, height, diameter, total number of seeds and percentage of viable seeds per fruit; number of embryos per seed, mass of one thousand seeds, number of seeds in 1.0 kg, final emergence rate, number of seedlings per seed, polyembryony rate, emergence speed index and seedling height at 60 days after sowing. For fruit size, the highest values were obtained for Swingle citrumelo. For number of embryos per seed, seedlings obtained through seed and polyembryony, citrandarin TSxPT 245 showed the highest values. Although citrandarin fruits had smaller size than fruits from commercial Rangpur lime and Swingle citrumelo rootstocks, characteristics related to seeds such as viability, polyembryony and emergence rate, were similar or superior, and can be considered potential new rootstocks for the production of citrus plants

PROTEIN MISFOLDING IN KENNEDY&#191;S DISEASE AND IN RELATED MOTOR NEURON DISEASES (MNDS)

Motor neuron diseases, like spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusions or aggregates of proteinaceous materials. In SBMA, inclusions are formed by testosterone dependent aggregates of mutant androgen receptor (AR) with an elongated polyglutamine tract (ARpolyQ), while in ALS inclusions contain several aggregated proteins including TDP43, ubiquilin, optineurin. Exceptions are familial ALS forms linked to superoxide dismutase 1 (SOD1) mutations, to mutated TDP43 and to C9ORF72 poly-dipeptides (DPRs), in which aggregates are mainly composed of mutant SOD1, mutant TDP43 or DPRs, respectively. In general, protein aggregation is due to generation of aberrant protein conformations (misfolding) combined to a failure, in neuronal cells, of the protein quality control (PQC) system, which may be insufficient to correctly remove the misfolded proteins. In other target tissue, such as the muscles, a different physiological PQC regulation may be helpful to remove misfolded proteins related to MNDs. The PQC system requires the activities of chaperones, degradative systems ubiquitin- proteasome (UPS) and autophagy. After misfolded protein recognition by chaperones, the dynein motor complex plays a crucial role to efficiently remove these species via autophagy, transporting them to autophagosome and assisting autophagosome- lysosome fusion. In this thesis, I have investigated the implications of protein misfolding in SBMA and in ALS. Taking advantage of a comparative analysis of misfolded proteins response in skeletal muscle and in spinal cord of SMBA mice, we proved that autophagy is dramatically perturbed in muscles. Indeed, we found the up-regulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3). In addition, the chaperon small Heat Shock Protein B8 (HSPB8) and its co-chaperone BCL2-Associated Athanogene 3 (BAG3), required for autophagy, were robustly up-regulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Interestingly, the BAG3:BAG1 ratio, increased in muscle, suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Misfolded proteins, recognized by HSPB8-BAG3 complex, are actively transport by dynein to MTOC to be inserted in autophagosome and degraded by autophagy, Then, we analysed the role of dynein mediate transport in the autophagic removal of misfolded proteins. In immortalized motoneuronal NSC34 cells, we found that the reduction of dynein protein levels, obtained using a specific siRNA, resulted in autophagy inhibition and in unexpected testosterone dependent ARpolyQ aggregates reduction. Also, we found that pharmacological dynein inhibition, with erythro-9-(2- Hydroxy-3-nonyl) adenine hydrochloride (EHNA), in NSC34 cells expressing ARpolyQ, mutant SOD1, truncated TDP43 form or C9ORF72 DPRs, induced a great reduction of mutant protein aggregates, even in presence of an autophagy inhibitor (3-MA), but not of a proteasome inhibitor (MG132). By performing fractionation studies we found that EHNA increased the ARpolyQ levels in PBS and Triton-X100 fractions. Surprisingly, we found that ENHA effects were paralleled by an increased expression of BAG1, a co- chaperone which routes misfolded proteins to UPS, but not of BAG3 suggesting the prevalence of UPS functions. Indeed, when dynein activity was blocked, BAG3:BAG1 ratio was decreased, thus in favour of BAG1 expression, suggesting the involvement of the pro-degradative activity of BAG1 on ARpolyQ aggregates. Collectively, these data show that mutant ARpolyQ induces a potent autophagic response in muscle cells. This may be useful to evaluate the SBMA progression. In parallel, dynein blockage perturbs autophagy and modifies the response of PQC system to misfolded protein. This results in reduced aggregation of MNDs-related misfolded proteins, a phenomenon that may occurs via an increase in their solubility and the induction of UPS functions