Intangible resources and organization capital: measurement and economic evaluation

Intangible resources have raised the interests of scholars from different research areas due to their importance as crucial factors for firm performance; yet, contributions to this field still lack a theoretical framework. This research analyses the state-of-the-art results reached in the literature concerning intangibles, their main features and evaluation problems and models. In search for a possible theoretical framework, the research draws a kind of indirect analysis of intangibles through the theories of the firm, their critic and developments. The heterodox approaches of the evolutionary theory and resource-based view are indicated as possible frameworks. Based on this theoretical analysis, organization capital (OC) is identified, for its features, as the most important intangible for firm performance. Empirical studies on the relationship intangibles-firm performance have been sporadic and have failed to reach firm conclusions with respect to OC; in the attempt to fill this gap, the effect of OC is tested on a large sample of European firms using the Compustat Global database. OC is proxied by capitalizing an income statement item (Selling, General and Administrative expenses) that includes expenses linked to information technology, business process design, reputation enhancement and employee training. This measure of OC is employed in a cross-sectional estimation of a firm level production function - modeled with different functional specifications (Cobb-Douglas and Translog) - that measures OC contribution to firm output and profitability. Results are robust and confirm the importance of OC for firm performance.

Epatite E: ruolo del suino nella trasmissione dell'infezione all'uomo, studio di prevalenza in aree rurali della Bolivia

L’infezione da virus dell’ epatite E (HEV) nei suini e nell’uomo è stata segnalata in diversi Paesi. Nei suini, il virus causa infezioni asintomatiche, mentre nell’uomo è responsabile di epidemie di epatite ad andamento acuto nei Paesi a clima tropicale o subtropicale con condizioni igieniche scadenti, di casi sporadici in quelli sviluppati. HEV è stato isolato anche in diversi animali e l’analisi nucleotidica degli isolati virali di origine animale ha mostrato un elevato grado di omologia con i ceppi di HEV umani isolati nelle stesse aree geografiche, avvalorando l’ipotesi che l'infezione da HEV sia una zoonosi. In America del Sud HEV suino è stato isolato per la prima volta in suini argentini nel 2006, mentre solo dal 1998 esistono dati sull’ infezione da HEV nell’uomo in Bolivia. In questa indagine è stato eseguito uno studio di sieroprevalenza in due comunità rurali boliviane e i risultati sono stati confrontati con quelli dello studio di sieroprevalenza sopra menzionato condotto in altre zone rurali della Bolivia. Inoltre, mediante Nested RT-PCR, è stata verificata la presenza di HEV nella popolazione umana e suina. La sieroprevalenza per anticorpi IgG anti-HEV è risultata pari al 6,2%, molto simile a quella evidenziata nello studio precedente. La prevalenza maggiore (24%) si è osservata nei soggetti di età compresa tra 41 e 50 anni, confermando che l’ infezione da HEV è maggiore fra i giovani-adulti. La ricerca di anticorpi anti HEV di classe IgM eseguita su 52 sieri ha fornito 4 risultati positivi. Il genoma virale è stato identificato in uno dei 22 pool di feci umane e l'esame virologico di 30 campioni individuali fecali e 7 individuali di siero ha fornito rispettivamente risultati positivi in 4/30 e 1/7. La Nested RT-PCR eseguita sui 22 pool di feci suine ha dato esito positivo in 7 pool. L’analisi delle sequenze genomiche di tutti gli amplificati ha consentito di stabilire che gli isolati umani appartenevano allo stesso genotipo III di quelli suini e presentavano con questi una elevata omologia aminoacidica (92%).

L'epatite E nei suidi: epidemiologia, diagnosi e filogenesi

Hepatitis E is an infectious viral disease with clinical and morphological features of acute hepatitis. The aetiological agent is the Hepatitis E virus (HEV). The disease represents an important Public Health problem in developing countries where is frequently epidemic and primarily transmitted by fecal-oral route. In the last few years, a certain number of sporadic cases have been also described in industrialized countries, Italy included. A swine HEV was first identified in 1997 and is now considered an ubiquitous virus. Human and swine strains from the same geographical region have shown to have a high level of nucleotidic omology and in experimental infections, the possibility of interspecific transmission of swine strains to humans and of human strains to non-human primates has been demonstrated. Furthermore, some seroepidemiological studies have demonstrated that people working in contact with swine have a higher risk to get infected than normal blood donors. Recently, cases of HEV hepatitis have been directly associated to the ingestion of uncooked tissues from pigs, wild boar or deer and today the disease is considered an emerging zoonosis. The aims of this thesis were: evaluate HEV prevalence in Italian swine herds (both in fattening and in breeding animals); investigate the possibility of finding HEV in livers used for human consumption; investigate if there is any correlation between HEV infection and the presence of macroscopical lesions; investigate HEV prevalence in a demographic managed wild boar population; phylogenetically analyse viral strains identified. During an internship period at Veterinary Laboratories Agency (Weybridge, UK), furthermore, swine samples at different stages of production and slurry lagoons have been analysed. Six swine herds located in North Italy have been sampled at different stage of production. The overall prevalence resulted 42%, and both breeding and fattening animals were positive for HEV infection. A longitudinal study has been conducted in a herd across all stages of production until the slaughtering age. Livers have been collected from the animals at the abattoir and 11.8% of them were positive for HEV infection. No correlations have been identified between HEV infection and macroscopical lesions in pigs affected by different pathological conditions. Of 86 wild boars tested 22 (25%) were positive for HEV. Of the swine tested in UK 21,5 % and 2 of the 9 slurry lagoons (22,2%) were positive for HEV infection. All the strains identified belonged to genotype 3 and showed high percentages of nucleotidic identity with humans and swine strains identified in Europe. The high prevalence detected in these studies confirms the widespread diffusion of HEV in swine populations in Italy and in UK. Phylogenetical analysis of identified strains, similar to those identified in autochthonous human hepatitis E cases of the same geographical area, confirm the hypothesis that pigs can be a font of zoonotical infection. The finding that a fraction of the livers inserted in the food chain are positive for HEV infection it’s of some concern for Public Health. The finding of a high HEV prevalence in all examined farms, together with the observation that infection may be sub-clinical and affect animals at slaughtering age, raise concern because of the possible risk of transmission of HEV to humans by either direct contact with infected pigs, indirect contact with environment and working instruments contaminated with pig feces, or ingestion of contaminated undercooked meat.

Eterogeneità delle proprietà fisico – chimiche della proteina prionica patologica e variabilità fenotipica ceppo specifica nella malattia di Creutzfeldt – Jakob

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are neurodegenerative disorders that affect humans and mammals. Creutzfeldt-Jakob disease (CJD), the most common TSE in humans, can be sporadic (sCJD), genetic (gCJD), or acquired by infection. All TSEs are characterised by the accumulation of PrPSc, a misfolded form of the cellular protein PrPC. PrPSc is insoluble in detergents, partially resistant to proteolysis and shows a highly enriched β-sheet secondary structure. Six clinico-pathological phenotypes of sCJD have been characterized which correlate at the molecular level with two types (1 or 2) of PrPSc with distinctive physicochemical properties and the genotype at the polymorphic (methionine or valine) codon 129 of the prion protein gene. According to the protein-only hypothesis, which postulates that prions are composed exclusively of PrPSc, the strains of prions that are largely responsible for the wide spectrum of TSE phenotypes are enciphered in PrPSc conformation. In support to this view, studies mainly conducted in experimental scrapie, have shown that several prion strains can be identified based on distinguishing PrPSc biochemical properties. To further contribute to the understanding of the molecular basis of strains and to develop more sensitive strain typing assays in humans we have analyzed PrPSc biochemical properties in two experimental setting. In the first we compared the size of the core after protease digestion and the glycoform pattern of PrPSc before and after transmission of human prions to non human primates or bank voles, whereas in the second we analyzed the conformational stability of PrPSc associated with sCJD, vCJD or fCJD using guanidine hydrochloride (GdnHCl) as denaturant. Combining the results of the two studies, we were able to distinguish five human strains for at least one biochemical property. The present data extend our knowledge about the extent of strain variation and its relationship with PrPSc properties in human TSEs.

Epidemiologia e caratterizzazione molecolare di virus emergenti responsabili di Zoonosi: Calcivirus e Virus dell'Epatite E

Il virus dell’Epatite E (HEV) e i calicivirus (norovirus e sapovirus) causano rispettivamente epatite acuta e gastroenterite. Questi virus sono considerati agenti eziologici emergenti rappresentando un problema di sanità pubblica e di sicurezza alimentare. Per HEV, è ormai confermata la trasmissione zoonotica, e il suino è considerato il principale serbatoio asintomatico. Norovirus e sapovirus infettano sia i bambini che gli adulti. Sebbene questi virus siano stati identificati anche negli animali, la possibile trasmissione zoonotica non è stata dimostrata in modo conclusivo. Il lavoro sperimentale condotto durante il Dottorato di Ricerca è stato focalizzato sullo studio degli aspetti biologici ed epidemiologici dell’infezioni causate da HEV e da calicivirus. Per la prima volta in Italia, i risultati ottenuti hanno dimostrato la presenza del virus HEV nei fegati di suini in fase di macellazione ed hanno confermato, attraverso la ricerca di anticorpi, un’elevata esposizione degli animali al virus. Inoltre, mediante la produzione di antigeni e reattivi immunologici, sono stati messi a punto test diagnostici per la ricerca di anticorpi contro HEV nel suino e nei cinghiali. Il lavoro svolto per la ricerca di calicivirus nel suino e nel bovino ha dimostrato la circolazione dei sapovirus in popolazioni di suini asintomatici e la presenza di norovirus nei vitelli affetti da diarrea acuta.Sono stati inoltre sviluppati reattivi immunologici, utilizzando proteine del capside di norovirus umano e bovino espresse con il sistema ricombinante baculovirus. Questi hanno permesso di evidenziare la presenza di anticorpi contro norovirus umano e bovino, in sieri di veterinari professionalmente esposti. Inoltre, sono stati utilizzati per sviluppare metodi per la concentrazione dei virus da matrici a bassa concentrazione.Infine, le VLP sono state utilizzate per valutare l’attivazione del sistema immunitario umano ex vivo. I risultati hanno dimostrato che le VLP di NoV stimolano il sistema immunitario attivando risposte di tipo Th1 e Th2 .

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.

The KIT gene in familial mastocytosis

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

Genetic and environmental factors associated with cardiovascular diseases and acute myocardial infarction

Acute myocardial infarction (AMI) is a multifactorial disease with a complex pathogenesis where lifestyle, individual genetic background and environmental risk factors are involved. Altered inflammatory responses seems to be implicated in the pathogenesis of atherosclerosis. To understand which genes may predispose to increased risk of cardiovascular disease gene polymorphism of immune regulatory genes, and clinical events from the Offs of parents with an early AMI were investigated. Genetics data from Offs were compared with those obtained from healthy subjects and an independent cohort of patients with clinical sporadic AMI. Rates of clinical events during a 24 years follow up from Offs and from an independent Italian population survey were also evaluated. This study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-γ was indeed present in the Offs population. During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. In these patients with the genetic signature the EBV and HHV-6 herpes virus were also investigated and founded. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events. These data suggest that selected genes with immune regulatory functions and envoronmental factors are part of the complex genetic background contributing to familiarity for cardiovascular diseases.N

Operating System Contribution to Composable Timing Behaviour in High-Integrity Real-Time Systems

The development of High-Integrity Real-Time Systems has a high footprint in terms of human, material and schedule costs. Factoring functional, reusable logic in the application favors incremental development and contains costs. Yet, achieving incrementality in the timing behavior is a much harder problem. Complex features at all levels of the execution stack, aimed to boost average-case performance, exhibit timing behavior highly dependent on execution history, which wrecks time composability and incrementaility with it. Our goal here is to restitute time composability to the execution stack, working bottom up across it. We first characterize time composability without making assumptions on the system architecture or the software deployment to it. Later, we focus on the role played by the real-time operating system in our pursuit. Initially we consider single-core processors and, becoming less permissive on the admissible hardware features, we devise solutions that restore a convincing degree of time composability. To show what can be done for real, we developed TiCOS, an ARINC-compliant kernel, and re-designed ORK+, a kernel for Ada Ravenscar runtimes. In that work, we added support for limited-preemption to ORK+, an absolute premiere in the landscape of real-word kernels. Our implementation allows resource sharing to co-exist with limited-preemptive scheduling, which extends state of the art. We then turn our attention to multicore architectures, first considering partitioned systems, for which we achieve results close to those obtained for single-core processors. Subsequently, we shy away from the over-provision of those systems and consider less restrictive uses of homogeneous multiprocessors, where the scheduling algorithm is key to high schedulable utilization. To that end we single out RUN, a promising baseline, and extend it to SPRINT, which supports sporadic task sets, hence matches real-world industrial needs better. To corroborate our results we present findings from real-world case studies from avionic industry.

Chemopreventive effects of eicosapentaenoic acid free fatty acid in a murine model of colitis-associated colorectal cancer

Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyps formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA-FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control, resulted in the enrichment of Lactobacillus species in the gut microbiota and led to tumor suppressor miR34-a induction. In conclusion, our data suggest that EPA-FFA is an effective chemopreventive agent in CAC.

Studio sul ruolo dei fattori genetici coinvolti nella Valvola Aortica Bicuspide e/o nell'Aneurisma dell'Aorta Toracica

La Valvola Aortica Bicuspide (BAV) rappresenta la più comune anomalia cardiaca congenita, con un’incidenza dello 0,5%-2% nella popolazione generale. Si caratterizza per la presenza di due cuspidi valvolari anziché tre e comprende diverse forme. La BAV è frequentemente associata agli aneurismi dell’aorta toracica (TAA). La dilatazione dell’aorta espone al rischio di sviluppare le complicanze aortiche acute. Materiali e metodi Sono stati reclutati 20 probandi consecutivi sottoposti a chirurgia della valvola aortica e dell'aorta ascendente presso l'Unità di Chirurgia Cardiaca di Policlinico S.Orsola-Malpighi di TAA associata a BAV. Sono stati esclusi individui con una condizione sindromica predisponente l’aneurisma aortico. Ciascun familiare maggiorenne di primo grado è stato arruolato nello studio. L’analisi di mutazioni dell’intero gene ACTA2 è stata eseguita con la tecnica del “bidirectional direct sequencing”. Nelle forme familiari, l’intera porzione codificante del genoma è stata eseguita usando l’exome sequencing. Risultati Dopo il sequenziamento di tutti i 20 esoni e giunzioni di splicing di ACTA2 nei 20 probandi, non è stata individuata alcuna mutazione. Settantasette familiari di primo grado sono stati arruolati. Sono state identificate cinque forme familiari. In una famiglia è stata trovata una mutazione del gene MYH11 non ritenuta patogenetica. Conclusioni La mancanza di mutazioni, sia nelle forme sporadiche sia in quelle familiari, ci suggerisce che questo gene non è coinvolto nello sviluppo della BAV e TAA e, l’associazione che è stata riportata deve essere considerata occasionale. L’architettura genetica della BAV verosimilmente dovrebbe consistere in svariate differenti varianti genetiche che interagiscono in maniera additiva nel determinare un aumento del rischio.

Effect of host genotype and prion strain on the phenotypic heterogeneity of Creutzfeldt-Jakob disease: the peripheral nervous system involvement and the spectrum of the genetic form

The first study was designed to assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD). To this aim, we reviewed medical records of 117 sCJDVV2, 65 sCJDMV2K, and 121 sCJDMM(V)1 subjects for symptoms/signs and neurophysiological data. We looked for the presence of PrPSc in postmortem PNS samples from 14 subjects by western blotting and real-time quaking-induced conversion (RT-QuIC) assay. Seventy-five (41.2%) VV2-MV2K patients, but only 11 (9.1%) MM(V)1, had symptoms/signs suggestive of PNS involvement and neuropathy was documented in half of the VV2-MV2K patients tested. RT-QuIC was positive in all PNS samples, whereas western blotting detected PrPSc in the sciatic nerve in only one VV2 and one MV2K. These results support the conclusion that peripheral neuropathy, likely related to PrPSc deposition, belongs to the phenotypic spectrum of sCJDMV2K and VV2, the two variants linked to the V2 strain. The second study aimed to characterize the genetic/molecular determinants of phenotypic variability in genetic CJD (gCJD). To this purpose, we compared 157 cases of gCJD to 300 of sCJD. We analyzed: demographic aspects, neurological symptoms/signs, histopathologic features and biochemical characteristics of PrPSc. The results strongly indicated that the clinicopathological phenotypes of gCJD largely overlap with those of sCJD and that the genotype at codon 129 in cis with the mutation (i.e. haplotype) contributes more than the latter to the disease phenotype. Some mutations, however, cause phenotypic variations including haplotype-specific patterns of PrPSc deposition such as the “dense” synaptic pattern (E200K-129M), the intraneuronal dots (E200K-129V), and the linear stripes perpendicular to the surface in the molecular layer of cerebellum (OPRIs-129M). Overall, these results suggest that in gCJD PRNP mutations do not cause the emergence of novel prion strains, but rather confer increased susceptibility to the disease in conjunction with “minor” clinicopathological variations.

Circulation of canine viruses in free-ranging Italian wolves (Canis lupus italicus) from three Italian regions

In this study, the duodenum, spleen, tongue, and lungs were sampled from 56 Italian wolves who died between 2017 and 2020. The aim of the study was to evaluate the presence and spread of DNA and RNA viruses in the wolf population examined, relating the virological results to: year of sampling, region of origin, sex, age, season, genetic determination of the species, nutritional conditions, causes of death, matrices examined. In addition, the presence or absence of co-infections was evaluated. Through molecular methods, the presence of genomic DNA of three important DNA viruses was investigated, i.e.: Canine Parvovirus type 2 (CPV-2), Canine Adenovirus type 1 (CAdV-1), Canine Adenovirus type 2 (CAdV-2). Furthermore, the presence of genomic RNA of the important RNA viruses, Canine Enteric Coronavirus (CCoV) and Canine Distemper Virus (CDV), was also investigated. The results showed that the virus with the highest prevalence in the wolf population studied was CPV-2, found in 78.6% of subjects (44/56). The prevalence of CAdV was 17.9% (10/56), in particular CAdV-1 (12.5% - 7/56) and CAdV-2 (5.4% - 3/56). The results of the molecular investigations in RT-PCR of the two RNA viruses (CCoV and CDV) did not give positive results in the study population. In this study it was observed that the majority of wolves that resulted positive were in good nutritional conditions, thus excluding a direct cause of death from CPV-2, CAdV-1, and CAdV- 2 infections. Moreover, the prevalence obtained in this study suggests that, during the years here studied, the circulation of CAdV-1 and CAdV-2 in Italian wolves of the three sampled regions was sporadic, proving consistent with sporadic and short-lived introductions of the virus in these populations. However, the situation for CPV-2 is different as there was a circulation that suggests a pattern of continuous and lasting endemic exposure over time.

Comprehensive characterization of SDH-deficient GIST using NGS data and iPSC models

Gastrointestinal stromal tumors (GIST) are the most common di tumors of the gastrointestinal tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. The vast majority of GISTs (75–85% of GIST) harbor KIT or PDGFRA mutations. A small percentage of GIST (about 10‐15%) do not harbor any of these driver mutations and have historically been called wild-type (WT). Among them, from 20% to 40% show loss of function of the succinate dehydrogenase complex (SDH), also defined as SDH‐deficient GIST. SDH-deficient GISTs display distinctive clinical and pathological features, and can be sporadic or associated with Carney triad or Carney-Stratakis syndrome. These tumors arise most frequently in the stomach with predilection to distal stomach and antrum, have a multi-nodular growth, display a histological epithelioid phenotype, and present frequent lympho-vascular invasion. Occurrence of lymph node metastases and indolent course are representative features of SDH-deficient GISTs. This subset of GIST is known for the immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals the loss of function of the entire SDH-complex. The overall aim of my PhD project consists of the comprehensive characterization of SDH deficient GIST. Throughout the project, clinical, molecular and cellular characterizations were performed using next-generation sequencing technologies (NGS), that has the potential to allow the identification of molecular patterns useful for the diagnosis and development of novel treatments. Moreover, while there are many different cell lines and preclinical models of KIT/PDGFRA mutant GIST, no reliable cell model of SDH-deficient GIST has currently been developed, which could be used for studies on tumor evolution and in vitro assessments of drug response. Therefore, another aim of this project was to develop a pre-clinical model of SDH deficient GIST using the novel technology of induced pluripotent stem cells (iPSC).

Evaluation of the transcriptomic response of an Alzheimer's disease murine model induced at different ages: searching for predictors

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disease, characterized by the impairment of mnesic and cognitive functions, that represents the most frequent type of dementia in older people worldwide. Aging is the most important risk factor for the sporadic form of the pathology and it is associated to the progressive impairment of the proteostasis network. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of β-amyloid (Aβ) protein and phosphorylated-tau protein. Increasing proteins misfolding activates a specific cellular response known as Unfolded Protein response (UPR) which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR and aging process in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomers at 3 or 18 months. The oligomers injection in aged animals caused the increased of memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA-sequencing analysis was performed and the bioinformatic analysis showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The following analysis highlighted the significant dysregulation of the three branches of the UPR, the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker of the neurodegenerative process, which regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.