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Objectives: To identify predictors of remission and disease activity patterns in patients with rheumatoid arthritis (RA) using individual participant data (IPD) from clinical trials. Methods: Phase II and III clinical trials completed between 2002 and 2012 were identified by systematic literature review and contact with UK market authorisation holders. Anonymised baseline and follow-up IPD from non-biological arms were amalgamated. Multiple imputation was used to handle missing outcome and covariate information. Random effects logistic regression was used to identify predictors of remission, measured by the Disease Activity Score 28 (DAS28) at 6 months. Novel latent class mixed models characterised DAS28 over time. Results: IPD of 3290 participants from 18 trials were included. Of these participants, 92% received methotrexate (MTX). Remission rates were estimated at 8.4%(95%CI 7.4%to9.5%) overall, 17%(95%CI 14.8%to19.4%) for MTX-naïve patients with early RA and 3.2% (95% CI 2.4% to 4.3%) for those with prior MTX exposure at entry. In prior MTX-exposed patients, lower baseline DAS28 and MTX reinitiation were associated with remission. In MTX-naïve patients, being young, white, male, with better functional and mental health, lower baseline DAS28 and receiving concomitant glucocorticoids were associated with remission. Three DAS28 trajectory subpopulations were identified in MTX-naïve and MTX-exposed patients. A number of variables were associated with subpopulation membership and DAS28 levels within subpopulations. Conclusions: Predictors of remission differed between MTX-naïve and prior MTX-exposed patients at entry. Latent class mixed models supported differential non-biological therapy response, with three distinct trajectories observed in both MTX-naïve and MTX-exposed patients. Findings should be useful when designing future RA trials and interpreting results of biomarker studies.

Collaboration can be challenging; nevertheless, the emerging successes of large, multi-partner, multi-national cooperatives and research networks in the biomedical sector have sustained the appetite of academics and industry partners for developing and fostering new research consortia. This model has percolated down to national funding agencies across the globe, leading to funding for projects that aim to realise the true potential of genomic medicine in the 21st century and to reap the rewards of ‘big data’. In this Perspectives article, the experiences of the RA-MAP consortium, a group of more than 140 individuals affiliated with 21 academic and industry organizations that are focused on making genomic medicine in rheumatoid arthritis a reality are described. The challenges of multi-partner collaboration in the UK are highlighted and wide-ranging solutions are offered that might benefit large research consortia around the world.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; http://www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; http://www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Presence and intracellular distribution of phosphoinositide-specific phospholipase C, phosphatidylinositol 4,5-bisphosphate and protein kinase C have been investigated in rat maturing germ cells and spermatozoa. The isoforms beta 1 and gamma 1 of phosphoinositide-specific phospholipase C were immunologically identified and found to be predominantly nuclear or cytoplasmic and nuclear, respectively. The two enzymes were present in the maturing cell lineage of the seminiferous tubule, except for the nucleus of late spermatids, and absent in spermatozoa, in which, however, a phosphoinositide-specific phospholipase C activity persisted, due to yet uncharacterized enzyme(s). Protein kinase C paralleled these developmental changes, and was completely down-regulated in both total cell homogenates and isolated nuclei obtained from spermatozoa. On the contrary, phosphatidylinositol 4,5-bisphosphate, present at the nuclear level in all cell types, accumulated in the nuclei of late spermatids and spermatozoa. These data support the contention that the spermatozoon nucleus stores a lipid-dependent signaling apparatus which could be reactivated either during sperm maturation or at fertilization.

The complement system was examined in 16 patients with AIDS-related complex (ARC) (n = 5) and/or lymphoadenopathy syndrome (LAS) (n = 11). Of these patients 62.5% showed an impairment of classical and/or alternative pathway activity associated with the presence of cleavage fragments of C3 and/or B and a significant reduction of many complement factors. The data indicate pathological complement activation in these patients through the classical and/or alternative pathway. Complement activation was more severe in patients with ARC than in those with LAS, and greater in drug abusers than homosexuals. The lack of efficient complement in the patients can be considered an 'acquired complement deficiency' with possible importance in the failure to combat the HIV attack.

Il capitolo si inserisce quale introduzione storiografica al tema oggetto di una monografia open source patrocinata dalla Sidrea (Società Italiana di Ragioneria ed Economia Aziendale). Detta monografia è il frutto di una ricerca collettanea sulla riforma del bilancio civilistico ex DPR 139/2015. I singoli contributi della stessa riguardano infatti le singole aree del bilancio. Rispetto a questa complessiva ricerca della società accademica di settore, il saggio/capitolo in oggetto, a natura esplicitamente introduttiva, intende mostrare come la disciplina giuridica sia sempre stata influenzata da un dibattito dottrinale a monte di tipo economico-aziendale, questo in Italia particolarmente ricco. Esso, quindi, ripercorre questa storia del pensiero, con particolare riferimento ai temi delle valutazioni di bilancio, a partire dai pioneristici contributi del XVI/XVII secolo, a seguire con le Scuole Classiche ottocentesche di Ragioneria, a sviluppare i contributi dei più grandi Maestri del Novecento, fino ad approdare alle più recenti tendenze di dottrina e di ricerca in materia di valutazioni nel nostro Paese. In parallelo alla suddetta evoluzione dottrinaria è presentata criticamente l’evoluzione della normativa civile/commerciale, di cui il DPR 139/2015 rappresenta solo l’ultima pagina di storia: da qualche cenno alle regolamentazioni pre-unitarie, al codice di commercio del 1865, a quello del 1882, al codice civile del 1942, alla L.216/1974, al D. L.vo 127/1991 e via via agli altri interventi sino all’ultima novella oggetto dell’intera monografia.

Il patrimonio netto aziendale è una misurazione della ricchezza aziendale il cui ammontare sotto il profilo quantitativo discende dai criteri di valutazione adottati per le attività e le passività del bilancio. Si tratta, come noto, di un valore residuale pari alla differenza tra le attività di Stato patrimoniale e le passività. In altre parole, si può definire come l’importo che residua delle attività, dopo aver sottratto tutte le passività (IAS 1). Conseguentemente, le modifiche ai criteri di valutazione prodotte dal D.Lgs. n. 139/2015 si riflettono sull’ammontare del patrimonio netto aziendale. La dimensione quantitativa del patrimonio netto dipende però non soltanto dai criteri di valutazione adottati, ma anche dalle modalità di rappresentazione in bilancio delle operazioni aziendali.

il presente lavoro intende analizzare le caratteristiche peculiari delle banche territoriali, con riferimento non soltanto agli aspetti strettamente contabili e di bilancio, ma anche al ruolo istituzionale che hanno assunto nel loro particolare contesto storico, economico e sociale. Si tratta di un obiettivo di ricerca non riguardante esclusivamente gli aspetti ragionieristici, ma una più ampia indagine sulle caratteristiche di aziendalità (Anselmi 2014) delle suddette realtà bancarie. L’obiettivo è indagare come – in una prospettiva evolutiva – il ruolo, le politiche e gli aspetti contabili siano cambiati al variare delle condizioni dei contesti giuridico-istituzionali (come ad esempio le riforme di legge sul sistema bancario) o politici (l’unificazione italiana). Nei casi considerati sono state analizzate le principali dinamiche concernenti la fondazione e la prima organizzazione, le caratteristiche strutturali e i primi orientamenti strategici, anche considerando gli equilibri economici di lungo periodo (Giannessi 1961). Adottando una metodologia basata sul caso di studio, sono stati individuati alcuni istituti bancari a forte vocazione territoriale: la Cassa di Risparmio di Lucca, la Cassa di Risparmio di Livorno, la Cassa di Risparmio di Ravenna e la Banca San Paolo in Brescia.

The importance of the Vav family of signal transduction molecules in hematopoietic cells has long been acknowledged, even though its role and its regulatory mechanism are not completely understood. We have previously demonstrated that tyrosine-phosphorylated Vav, also located inside the nucleus of myeloid cells, is up-regulated during maturation of promyelocytic precursors induced by all-trans-retinoic acid (ATRA). Here, we report that the tyrosine phosphorylation of Vav during granulocytic maturation is dependent on the tyrosine kinase Syk and is essential for the morphological changes of the cell nucleus. These ATRA-induced events are independent on the guanine nucleotide exchange activity of Vav. We also found that, in differentiating cells, and in both cytoplasmic and nuclear compartments, tyrosine phosphorylated Vav associates with the regulatory subunit of phosphoinositide 3-kinase (PI 3-K). The Vav/p85 interaction is essential for the ATRA-induced PI 3-K activity and for association of PI 3-K with actin, particularly in the nucleus. Our data indicate an unprecedented crucial function for Vav in modulating the morphological maturation process of myeloid cells in a GDP-GTP exchange factor (GEF)-independent manner and suggest a role of Vav as an adaptor protein responsible of targeting PI 3-K to its intranuclear substrates.