From core rigidities to dynamic capabilities: the role of external knowledge. A multiple case study

This study focuses on the processes of change that firms undertake to overcome conditions of organizational rigidity and develop new dynamic capabilities, thanks to the contribution of external knowledge. When external contingencies highlight firms’ core rigidities, external actors can intervene in change projects, providing new competences to firms’ managers. Knowledge transfer and organizational learning processes can lead to the development of new dynamic capabilities. Existing literature does not completely explain how these processes develop and how external knowledge providers, as management consultants, influence them. Dynamic capabilities literature has become very rich in the last years; however, the models that explain how dynamic capabilities evolve are not particularly investigated. Adopting a qualitative approach, this research proposes four relevant case studies in which external actors introduce new knowledge within organizations, activating processes of change. Each case study consists of a management consulting project. Data are collected through in-depth interviews with consultants and managers. A large amount of documents supports evidences from interviews. A narrative approach is adopted to account for change processes and a synthetic approach is proposed to compare case studies along relevant dimensions. This study presents a model of capabilities evolution, supported by empirical evidence, to explain how external knowledge intervenes in capabilities evolution processes: first, external actors solve gaps between environmental demands and firms’ capabilities, changing organizational structures and routines; second, a knowledge transfer between consultants and managers leads to the creation of new ordinary capabilities; third, managers can develop new dynamic capabilities through a deliberate learning process that internalizes new tacit knowledge from consultants. After the end of the consulting project, two elements can influence the deliberate learning process: new external contingencies and changes in the perceptions about external actors.

Modulation of hypoxia-inducible factors as a therapeutic target for multiple myeloma

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in survival and is associated with poor prognosis in solid tumors. The role of HIF-1α in multiple myeloma is not completely known. In the present study, we explored the effect of EZN2968, an locked nucleic acid antisense oligonucleotide against HIF-1α, as a molecular target in MM. A panel of MM cell lines and primary samples from MM patients were cultured in vitro in the presence of EZN2968 . Under normoxia culture condition, HIF-1α mRNA and protein expression was detectable in all MM cell lines and in CD138+ cells from newly diagnosed MM patients samples. Significant up-regulation of HIF-1α protein expression was observed after incubation with IL6 or IGF-I, confirming that HIF-1α can be further induced by biological stimuli. EZN2968 efficiently induces a selective and stable down-modulation of HIF-1α and decreased the secretion of VEGF released by MM cell. Treatment with EZN2968 gave rise to a progressive accumulation of cells in the S and subG0 phase. The analysis of p21, a cyclin-dependent kinase inhibitors controlling cell cycle check point, shows upregulation of protein levels. These results suggest that HIF-1α inhibition is sufficient for cell cycle arrest in normoxia, and for inducing an apoptotic pathways.. In the presence of bone marrow microenvironment, HIF-1α inhibition blocks MAPK kinase pathway and secretion of pro-surviaval cytokines ( IL6,VEGF,IL8) In this study we provide evidence that HIF-1α, even in the absence of hypoxia signal, is expressed in MM plasma cells and further inducible by bone marrow milieu stimuli; moreover its inhibition is sufficient to induce a permanent cell cycle arrest. Our data support the hypothesis that HIF-1α inhibition may suppress tumor growth by preventing proliferation of plasma cells through p21 activation and blocking pro-survival stimuli from bone marrow microenvironment.

The impact of polymorphisms in P-gp, DNA repair and folic acid metabolism genes in newly diagnosed multiple myeloma patients treated with thalidomide plus dexamethasone, with or without bortezomib

The principle aim of this study was to investigate biological predictors of response and resistance to multiple myeloma treatment. Two hypothesis had been proposed as responsible of responsiveness: SNPs in DNA repair and Folate pathway, and P-gp dependent efflux. As a first objective, panel of SNPs in DNA repair and Folate pathway genes, were analyzed. It was a retrospective study in a group of 454, previously untreated, MM patients enrolled in a randomized phase III open-label study. Results show that some SNPs in Folate pathway are correlated with response to MM treatment. MTR genotype was associated with favorable response in the overall population of MM patients. However, this relation, disappear after adjustment for treatment response. When poor responder includes very good partial response, partial response and stable/progressive disease MTFHR rs1801131 genotype was associated with poor response to therapy. This relation - unlike in MTR – was still significant after adjustment for treatment response. Identification of this genetic variant in MM patients could be used as an independent prognostic factor for therapeutic outcome in the clinical practice. In the second objective, basic disposition characteristics of bortezomib was investigated. We demonstrated that bortezomib is a P-gp substrate in a bi-directional transport study. We obtain apparent permeability rate values that together with solubility values can have a crucial implication in better understanding of bortezomib pharmacokinetics with respect to the importance of membrane transporters. Subsequently, in view of the importance of P-gp for bortezomib responsiveness a panel of SNPs in ABCB1 gene - coding for P-gp - were analyzed. In particular we analyzed five SNPs, none of them however correlated with treatment responsiveness. However, we found a significant association between ABCB1 variants and cytogenetic abnormalities. In particular, deletion of chromosome 17 and t(4;14) translocation were present in patients harboring rs60023214 and rs2038502 variants respectively.

Integration of cognitive and affective processes in perception and decision-making

The relationship between emotion and cognition is a topic that raises great interest in research. Recently, a view of these two processes as interactive and mutually influencing each other has become predominant. This dissertation investigates the reciprocal influences of emotion and cognition, both at behavioral and neural level, in two specific fields, such as attention and decision-making. Experimental evidence on how emotional responses may affect perceptual and attentional processes has been reported. In addition, the impact of three factors, such as personality traits, motivational needs and social context, in modulating the influence that emotion exerts on perception and attention has been investigated. Moreover, the influence of cognition on emotional responses in decision-making has been demonstrated. The current experimental evidence showed that cognitive brain regions such as the dorsolateral prefrontal cortex are causally implicated in regulation of emotional responses and that this has an effect at both pre and post decisional stages. There are two main conclusions of this dissertation: firstly, emotion exerts a strong influence on perceptual and attentional processes but, at the same time, this influence may also be modulated by other factors internal and external to the individuals. Secondly, cognitive processes may modulate emotional prepotent responses, by serving a regulative function critical to driving and shaping human behavior in line with current goals.

Multiple stellar populations in globular clusters with photometry and low resolution spectroscopy

Our view of Globular Clusters has deeply changed in the last decade. Modern spectroscopic and photometric data have conclusively established that globulars are neither coeval nor monometallic, reopening the issue of the formation of such systems. Their formation is now schematized as a two-step process, during which the polluted matter from the more massive stars of a first generation gives birth, in the cluster innermost regions, to a second generation of stars with the characteristic signature of fully CNO-processed matter. To date, star-to-star variations in abundances of the light elements (C, N, O, Na) have been observed in stars of all evolutionary phases in all properly studied Galactic globular clusters. Multiple or broad evolutionary sequences have also been observed in nearly all the clusters that have been observed with good signal-to-noise in the appropriate photometric bands. The body of evidence suggests that spreads in light-element abundances can be fairly well traced by photometric indices including near ultraviolet passbands, as CNO abundance variations affect mainly wavelengths shorter than ~400 nm owing to the rise of some NH and CN molecular absorption bands. Here, we exploit this property of near ultraviolet photometry to trace internal chemical variations and combined it with low resolution spectroscopy aimed to derive carbon and nitrogen abundances in order to maximize the information on the multiple populations. This approach has been proven to be very effective in (i) detecting multiple population, (ii) characterizing their global properties (i.e., relative fraction of stars, location in the color-magnitude diagram, spatial distribution, and trends with cluster parameters) and (iii) precisely tagging their chemical properties (i.e., extension of the C-N anticorrelation, bimodalities in the N content).

Longitudinal evolution of cognitive functions in patients with multiple system atrophy: a prospective study

Introduction and Background: Multiple system atrophy (MSA) is a sporadic, adult-onset, progressive neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, and autonomic failure. We investigated cognitive functions longitudinally in a group of probable MSA patients, matching data with sleep parameters. Patients and Methods: 10 patients (7m/3f) underwent a detailed interview, a general and neurological examination, laboratory exams, MRI scans, a cardiovascular reflexes study, a battery of neuropsychological tests, and video-polysomnographic recording (VPSG). Patients were revaluated (T1) a mean of 16±5 (range: 12-28) months after the initial evaluation (T0). At T1, the neuropsychological assessment and VPSG were repeated. Results: The mean patient age was 57.8±6.4 years (range: 47-64) with a mean age at disease onset of 53.2±7.1 years (range: 43-61) and symptoms duration at T0 of 60±48 months (range: 12-144). At T0, 7 patients showed no cognitive deficits while 3 patients showed isolated cognitive deficits. At T1, 1 patient worsened developing multiple cognitive deficits from a normal condition. At T0 and T1, sleep efficiency was reduced, REM latency increased, NREM sleep stages 1-2 slightly increased. Comparisons between T1 and T0 showed a significant worsening in two tests of attention and no significant differences of VPSG parameters. No correlation was found between neuropsychological results and VPSG findings or RBD duration. Discussion and Conclusions: The majority of our patients do not show any cognitive deficits at T0 and T1, while isolated cognitive deficits are present in the remaining patients. Attention is the cognitive function which significantly worsened. Our data confirm the previous findings concerning the prevalence, type and the evolution of cognitive deficits in MSA. Regarding the developing of a condition of dementia, our data did not show a clear-cut diagnosis of dementia. We confirm a mild alteration of sleep structure. RBD duration does not correlate with neuropsychological findings.

Integration of MFA and LCA methodologies: the anthropogenic aluminium cycle in Italy

MFA and LCA methodologies were applied to analyse the anthropogenic aluminium cycle in Italy with focus on historical evolution of stocks and flows of the metal, embodied GHG emissions, and potentials from recycling to provide key features to Italy for prioritizing industrial policy toward low-carbon technologies and materials. Historical trend series were collected from 1947 to 2009 and balanced with data from production, manufacturing and waste management of aluminium-containing products, using a ‘top-down’ approach to quantify the contemporary in-use stock of the metal, and helping to identify ‘applications where aluminium is not yet being recycled to its full potential and to identify present and future recycling flows’. The MFA results were used as a basis for the LCA aimed at evaluating the carbon footprint evolution, from primary and electrical energy, the smelting process and the transportation, embodied in the Italian aluminium. A discussion about how the main factors, according to the Kaya Identity equation, they did influence the Italian GHG emissions pattern over time, and which are the levers to mitigate it, it has been also reported. The contemporary anthropogenic reservoirs of aluminium was estimated at about 320 kg per capita, mainly embedded within the transportation and building and construction sectors. Cumulative in-use stock represents approximately 11 years of supply at current usage rates (about 20 Mt versus 1.7 Mt/year), and it would imply a potential of about 160 Mt of CO2eq emissions savings. A discussion of criticality related to aluminium waste recovery from the transportation and the containers and packaging sectors was also included in the study, providing an example for how MFA and LCA may support decision-making at sectorial or regional level. The research constitutes the first attempt of an integrated approach between MFA and LCA applied to the aluminium cycle in Italy.

Reverse Engineering tools: development and experimentation of innovative methods for physical and geometrical data integration and post-processing

In recent years, the use of Reverse Engineering systems has got a considerable interest for a wide number of applications. Therefore, many research activities are focused on accuracy and precision of the acquired data and post processing phase improvements. In this context, this PhD Thesis deals with the definition of two novel methods for data post processing and data fusion between physical and geometrical information. In particular a technique has been defined for error definition in 3D points’ coordinates acquired by an optical triangulation laser scanner, with the aim to identify adequate correction arrays to apply under different acquisition parameters and operative conditions. Systematic error in data acquired is thus compensated, in order to increase accuracy value. Moreover, the definition of a 3D thermogram is examined. Object geometrical information and its thermal properties, coming from a thermographic inspection, are combined in order to have a temperature value for each recognizable point. Data acquired by an optical triangulation laser scanner are also used to normalize temperature values and make thermal data independent from thermal-camera point of view.

Who can (not) be Greek? Citizenship, Identity and Belonging among youth of sub-Saharan African background in Athens

‘Who can be Greek?’ This was the question posed to the Greek society for the first time before the implementation of the Act 3838 in March 2010 which gave the right to access the Greek citizenship -under specific preconditions- to all children of legal migrants born or schooled in Greece. This change of the Nationality Code in order to include all those children was coincided by the economic crisis resulting into the rise of xenophobia, racism and extreme-right rhetoric. The outcome was the cancellation of the Act 3838 by the State Council in February 2013. Under this particular framework, the notions of identity and belonging formed among the youth of African background in Athens are explored. The ways those youngsters perceive not only themselves but also their peers, their countries of origin and the country they live in, are crucial elements of their self-identification. Researches have shown that the integration of the second generation is highly connected to their legal and social status. However, integration is a rather complex process, influenced and shaped by many variables and multiple factors. It is not linear; therefore, its outcomes are difficult to be predicted. Yet, I argue that citizenship acquisition facilitates the process as it transforms those children from ‘aliens’ to ‘citizens’. How these youngsters are perceived by the majority society and the State is one of the core questions of the research, focusing on the imposed dual ‘otherness’ they are subject to. On the one hand, they have to deal with the ‘otherness’ originating from the migrant status inherited to them by their parents, and on the other with the ‘otherness’ deriving from their different phenotypic characteristics. Race matters and becomes a means of discrimination against youth of African background who are perceived as inassimilable and ‘forever others’.

The search for Multiple Myeloma Stem cells: molecular characterization and self-renewal mechanisms involved in the disease persistence

The existence of Multiple Myeloma Stem cells (MMSCs)is supposed to be one of the major causes of MM drug-resistance. However, very little is known about the molecular characteristics of MMSCs, even if some studies suggested that these cells resembles the memory B cells. In order to molecularly characterize MMSCs, we isolated the 138+138- population. For each cell fraction we performed a VDJ rearrangement analysis. The complete set of aberrations were performed by SNP Array 6.0 and HG-U133 Plus 2.0 microarray analyses (Affymetrix). The VDJ rearrangement analyses confirmed the clonal relationship between the 138+ clone and the immature clone. Both BM and PBL 138+ clones showed exactly the same genomic macroalterations. In the BM and PBL 138-19+27+ cell fractions several micro-alterations (range: 1-350 Kb) unique of the memory B cells clone were highlighted. Any micro-alterations detected were located out of any genomic variants region and are presumably associated to the MM pathogenesis, as confirmed by the presence of KRAS, WWOX and XIAP genes among the amplified regions. To get insight into the biology of the clonotypic B cell population, we compared the gene expression profile of 8 MM B cells samples 5 donor B cells vs, thus showing a differential expression of 11480 probes (p-value: <0,05). Among the self-renewal mechanisms, we observed the down-regulation of Hedgehog pathway and the iperactivation of Notch and Wnt signaling. Moreover, these immature cells showed a particular phenotype correlated to resistance to proteasome inhibitors (IRE1α-XBP1: -18.0; -19.96. P<0,05). Data suggested that the MM 138+ clone might resume the end of the complex process of myelomagenesis, whereas the memory B cells have some intriguing micro-alterations and a specific transcriptional program, supporting the idea that these post germinal center cells might be involved in the transforming event that originate and sustain the neoplastic clone.

New computational biology tools for the systematic analysis of the structure and expression of human genes

From the late 1980s, the automation of sequencing techniques and the computer spread gave rise to a flourishing number of new molecular structures and sequences and to proliferation of new databases in which to store them. Here are presented three computational approaches able to analyse the massive amount of publicly avalilable data in order to answer to important biological questions. The first strategy studies the incorrect assignment of the first AUG codon in a messenger RNA (mRNA), due to the incomplete determination of its 5' end sequence. An extension of the mRNA 5' coding region was identified in 477 in human loci, out of all human known mRNAs analysed, using an automated expressed sequence tag (EST)-based approach. Proof-of-concept confirmation was obtained by in vitro cloning and sequencing for GNB2L1, QARS and TDP2 and the consequences for the functional studies are discussed. The second approach analyses the codon bias, the phenomenon in which distinct synonymous codons are used with different frequencies, and, following integration with a gene expression profile, estimates the total number of codons present across all the expressed mRNAs (named here "codonome value") in a given biological condition. Systematic analyses across different pathological and normal human tissues and multiple species shows a surprisingly tight correlation between the codon bias and the codonome bias. The third approach is useful to studies the expression of human autism spectrum disorder (ASD) implicated genes. ASD implicated genes sharing microRNA response elements (MREs) for the same microRNA are co-expressed in brain samples from healthy and ASD affected individuals. The different expression of a recently identified long non coding RNA which have four MREs for the same microRNA could disrupt the equilibrium in this network, but further analyses and experiments are needed.

Advanced modelling of time domain electromagnetic data with updated hydrogeological interpretations

Several countries have acquired, over the past decades, large amounts of area covering Airborne Electromagnetic data. Contribution of airborne geophysics has dramatically increased for both groundwater resource mapping and management proving how those systems are appropriate for large-scale and efficient groundwater surveying. We start with processing and inversion of two AEM dataset from two different systems collected over the Spiritwood Valley Aquifer area, Manitoba, Canada respectively, the AeroTEM III (commissioned by the Geological Survey of Canada in 2010) and the “Full waveform VTEM” dataset, collected and tested over the same survey area, during the fall 2011. We demonstrate that in the presence of multiple datasets, either AEM and ground data, due processing, inversion, post-processing, data integration and data calibration is the proper approach capable of providing reliable and consistent resistivity models. Our approach can be of interest to many end users, ranging from Geological Surveys, Universities to Private Companies, which are often proprietary of large geophysical databases to be interpreted for geological and\or hydrogeological purposes. In this study we deeply investigate the role of integration of several complimentary types of geophysical data collected over the same survey area. We show that data integration can improve inversions, reduce ambiguity and deliver high resolution results. We further attempt to use the final, most reliable output resistivity models as a solid basis for building a knowledge-driven 3D geological voxel-based model. A voxel approach allows a quantitative understanding of the hydrogeological setting of the area, and it can be further used to estimate the aquifers volumes (i.e. potential amount of groundwater resources) as well as hydrogeological flow model prediction. In addition, we investigated the impact of an AEM dataset towards hydrogeological mapping and 3D hydrogeological modeling, comparing it to having only a ground based TEM dataset and\or to having only boreholes data.

La governance del sociosanitario in Emilia Romagna: Esperienze e prospettive

In un contesto dominato da invecchiamento della popolazione, prevalenza della cronicità e presenza crescente di pazienti multiproblematici e non autosufficienti è indispensabile spostare il baricentro delle cure dall'acuzie alla cronicità, e quindi assicurare la continuità e la coerenza fra i diversi setting di cura, sia sanitari che socio-sanitari (ospedale, servizi sanitari territoriali, domicilio, strutture residenziali di Long term care). Dall'analisi della letteratura emerge che il maggiore ostacolo a realizzare questa continuità è rappresentato dalla presenza, caratteristica del sistema di welfare italiano, di molteplici attori e strutture con competenze, obiettivi e funzioni diverse e separate, e la raccomandazione di lavorare per l'integrazione contemporaneamente su più livelli: - normativo-istituzionale - programmatorio - professionale e gestionale Il sistema della "governance" realizzato in Emilia-Romagna per l'integrazione socio-sanitaria è stato valutato alla luce di queste raccomandazioni, seguendo il modello della Realist evaluation per i Social complex interventions: enucleando le "teorie" alla base dell'intervento ed analizzando i diversi step della sua implementazione. Alla luce di questa valutazione, il modello della "governance" è risultato coerente con le indicazioni delle linee guida, ed effettivamente capace di produrre risultati al fine della continuità e della coerenza fra cure sanitarie e assistenza sociale e sanitaria complessa. Resta da realizzare una valutazione complessiva dell'impatto su efficacia, costi e soddisfazione dei pazienti.

The impact of intraclonal heterogeneity on the outcomes of Multiple Myeloma patients treated with new drugs

Understanding the biology of Multiple Myeloma (MM) is of primary importance in the struggle to achieve a cure for this yet incurable neoplasm. A better knowledge of the mechanism underlying the development of MM can guide us in the development of new treatment strategies. Studies both on solid and haematological tumours have shown that cancer comprises a collection of related but subtly different clones, a feature that has been termed “intra-clonal heterogeneity”. This intra-clonal heterogeneity is likely, from a “Darwinian” natural selection perspective, to be the essential substrate for cancer evolution, disease progression and relapse. In this context the critical mechanism for tumour progression is competition between individual clones (and cancer stem cells) for the same microenvironmental “niche”, combined with the process of adaptation and natural selection. The Darwinian behavioural characteristics of cancer stem cells are applicable to MM. The knowledge that intra-clonal heterogeneity is an important feature of tumours’ biology has changed our way to addressing cancer, now considered as a composite mixture of clones and not as a linear evolving disease. In this variable therapeutic landscape it is important for clinicians and researchers to consider the impact that evolutionary biology and intra-clonal heterogeneity have on the treatment of myeloma and the emergence of treatment resistance. It is clear that if we want to effectively cure myeloma it is of primarily importance to understand disease biology and evolution. Only by doing so will we be able to effectively use all of the new tools we have at our disposal to cure myeloma and to use treatment in the most effective way possible. The aim of the present research project was to investigate at different levels the presence of intra-clonal heterogeneity in MM patients, and to evaluate the impact of treatment on clonal evolution and on patients’ outcomes.

Learning Methods and Algorithms for Semantic Text Classification across Multiple Domains

Information is nowadays a key resource: machine learning and data mining techniques have been developed to extract high-level information from great amounts of data. As most data comes in form of unstructured text in natural languages, research on text mining is currently very active and dealing with practical problems. Among these, text categorization deals with the automatic organization of large quantities of documents in priorly defined taxonomies of topic categories, possibly arranged in large hierarchies. In commonly proposed machine learning approaches, classifiers are automatically trained from pre-labeled documents: they can perform very accurate classification, but often require a consistent training set and notable computational effort. Methods for cross-domain text categorization have been proposed, allowing to leverage a set of labeled documents of one domain to classify those of another one. Most methods use advanced statistical techniques, usually involving tuning of parameters. A first contribution presented here is a method based on nearest centroid classification, where profiles of categories are generated from the known domain and then iteratively adapted to the unknown one. Despite being conceptually simple and having easily tuned parameters, this method achieves state-of-the-art accuracy in most benchmark datasets with fast running times. A second, deeper contribution involves the design of a domain-independent model to distinguish the degree and type of relatedness between arbitrary documents and topics, inferred from the different types of semantic relationships between respective representative words, identified by specific search algorithms. The application of this model is tested on both flat and hierarchical text categorization, where it potentially allows the efficient addition of new categories during classification. Results show that classification accuracy still requires improvements, but models generated from one domain are shown to be effectively able to be reused in a different one.