Clinicopathological and molecular characterization of gastroesophageal junction (GEJ) adenocarcinoma before age of 40 years

Gastroesophageal junction (GEJ) adenocarcinoma are uncommon before age of 40 years. While certain clinical, pathological and molecular features of GEJ adenocarcinoma in older patients have been extensively studied, these characteristics in the younger population remain to be determined. In the recent literature, a high sensitivity and specificity for the detection of dysplasia and esophageal adenocarcinoma was demonstrated by using multicolor fluorescence in situ hybridization (FISH) DNA probe set specific for the locus specific regions 9p21 (p16), 20q13.2 and Y chromosome. We evaluated 663 patients with GEJ adenocarcinoma and further divided them into 2 age-groups of or= 50 years, rispectively. FISH with selected DNA probe for Y chromosome, locus 9p21 (p16), and locus 20q13.2 was investigated with formalin fixed and parassin embedded tissue from surgical resections of 17 younger and 11 older patients. Signals were counted in > 100 cells with each given histopathological category. The chromosomal aberrations were then compared in the 2 age-groups with the focus on uninvolved squamous and columnar epithelium, intestinal metaplasia (Barrett's mucosa), glandular dysplasia, and adenocarcinoma. Comparisons were performed by the X2 test, Fisher's exact test, Student's t-test and Mann-Whitney U-test as appropriate. Survival was estimated by the Kaplan-Meier method with univariate analysis by the log-rank. Significance was taken at the 5% level. There was no difference in the surgical technique applied in both age groups and most patients underwent Ivor Lewis esophagectomy. Among clinical variables there was a higher incidence of smocking history in older patient group. We identified a progressive loss of Y chromosome from benign squamos epithelium to Barrett's mucosa and glandular dysplasia, and, ultimately, to a near complete loss in adenocarcinoma in both age groups. The young group revealed significantly more losses of 9p21 in both benign and neoplastic cells when compared to the older patients group. In addition, we demonstrated an increase in the percentage of cells showing gain of locus 20q13.2 with progression from benign epithelium through dysplasia to adenocarcinoma with almost the same trend in both the young and the older patients. When compared with the older age-group, younger patients with GEJ adenocarcinoma possess similar known demographics, environmental factors, clinical, and pathologic characteristics. The most commonly detected genetic aberrations of progressive Y chromosomal loss, 9p21 locus loss, and 20q13 gains were similar in the younger and older patients. However the rate of loss of 9p21 is significantly higher in young patients, in both the benign and the neoplastic cells. The loss of 9p21, and possibly, the subsequent inactivation of p16 gene may be one of the molecular mechanisms responsible for the accelerated neoplastic process in young patients.

Rising China and Internet governance: Multistakeholderism, fragmentation and the Liberal Order in the age of digital sovereignty

In its open and private-based dimension, the Internet is the epitome of the Liberal International Order in its global spatial dimension. Therefore, normative questions arise from the emergence of powerful non-liberal actors such as China in Internet governance. In particular, China has supported a UN-based multilateral Internet governance model based on state sovereignty aimed at replacing the existing ICANN-based multistakeholder model. While persistent, this debate has become less dualistic through time. However, fear of Internet fragmentation has increased as the US-China technological competition grew harsher. This thesis inquires “(To what extent) are Chinese stakeholders reshaping the rules of Global Internet Governance?”. This is further unpacked in three smaller questions: (i) (To what extent) are Chinese stakeholders contributing to increased state influence in multistakeholder fora?; (ii) (how) is China contributing to Internet fragmentation?; and (iii) what are the main drivers of Chinese stakeholders’ stances? To answer these questions, Chinese stakeholders’ actions are observed in the making and management of critical Internet resources at the IETF and ICANN respectively, and in mobile connectivity standard-making at 3GPP. Through the lens of norm entrepreneurship in regime complexes, this thesis interprets changes and persistence in the Internet governance normative order and Chinese attitudes towards it. Three research methods are employed: network analysis, semi-structured expert interviews, and thematic document analysis. While China has enhanced state intervention in several technological fields, fostering debates on digital sovereignty, this research finds that the Chinese government does not exert full control on its domestic private actors and concludes that Chinese stakeholders have increasingly adapted to multistakeholder Internet governance as they grew influential within it. To enhance control over Internet-based activities, the Chinese government resorted to regulatory and technical control domestically rather than establishing a splinternet. This is due to Chinese stakeholders’ interest in retaining the network benefits of global interconnectivity.

Sealing practices in the Near East during the Late Bronze II period: administration and trade in the age of internationalism

This PhD research investigates sealing practices in the Near East during the Late Bronze II period (ca. 1375-1175 BCE). Sealings from archaeological contexts in the Southern Levant, North Syria, Upper and Lower Mesopotamia and South-Western Iran are taken under consideration and analyzed on multiple aspects at local, regional, and international levels. The contextual, functional, and iconographic analysis of these materials, in fact, allows to reconstruct the nature of the transactions and the agents involved in the sealing operations within local administrative systems, highlighting at the same time aspects of inter-regional interactions during the age of internationalism. Following a survey of the available evidence, a corpus consisting of 1845 records from 28 different sites across the ANE, has been filed using MS Access and MS Excel, including 740 unpublished sealing from Karkemish. Among this large evidence, the corpus of recently discovered sealings from Karkemish and the other scattered sealings from the North Syrian provinces, for instance, provide insights on the core-periphery relationships under the Hittite Empire; while the deposit from Building P at Tell Sheikh Hamad, that of the Middle Assyrian houses at Tell Fekheriye, and of the dunnu of Tell Sabi Abyad, significantly contributes to defining the administration of provinces within the Middle Assyrian state and the regional circulation of good. The less extensive evidence from South Mesopotamia under the Kassite rule and from Middle Elamite contexts in South-Western Iran somewhat contribute as well to the understanding of sealing practices in the LB II period. The South Levantine kingdoms, on the other hand, seems participates to the Egyptian regional network of exchanges and sealing practices.

Artisanal food productions of animal origin: exploring food safety in the age of Whole Genome Sequencing

The artisanal food chain is enriched by a wide diversity of local food productions with delightful organoleptic characteristics and valuable nutritional properties. Despite their increasing worldwide popularity and appeal, several food safety challenges are addressed in artisanal facilities context suffering from less standardized processing conditions. In such scenario, recent advances in molecular typing and genomic surveillance (e.g., Whole Genome Sequencing [WGS]) represent an unprecedent solution capable of inferring sources of contamination as well as contributing to food safety along the artisanal food continuum. The overall objective of this PhD thesis was to explore potential microbial hazards among different artisanal food productions of animal origins (dairy and meat-derived) typical of the food culture and heritage landscape belonging to Mediterranean countries. Three different studies were then carried out, specifically focussing on: 1) compare the seasonal variability of microbiological quality and potential occurrence of microbial hazards in two batches of Italian artisanal fermented dairy and meat productions; 2) Investigate genetic relationships as well as virulome and resistome of foodborne pathogens isolated within dairy and meat-derived productions located in Italy, Spain, Portugal and Morocco; 3) investigate the population structure, virulome, resistome and mobilome of Klebsiella spp. isolates collected from study 1, including an extended range of public sequences.