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The aim of this study is to analyse the volatility of agricultural commodity prices and assess the effectiveness of supply chain contracts as possible tools to prevent it. The study refers to the cereal sector, which is of vital importance for the agri-food system of the Mediterranean area. Since Italy is the world’s largest producer of durum wheat semolina, the proper functioning of the Italian durum wheat supply chain is central to this investigation. The study was conducted following two different paths of analysis: (1) the calculation of volatility indices using annual and monthly data of durum wheat prices, both organic and industrial, observed in the Bologna Commodity Exchange (AGER); (2) the analysis of two organic durum wheat supply chain contracts, defined by a cooperative involving hundreds of Italian farms mainly from the Marche region and by an agricultural consortium operating in the Adriatic regions. Despite the limited number of cases examined, the present study shows how supply chain contracts can be valid tools for building stable relationships between the various players, from production to processing and distribution, guaranteeing farms fairer and more remunerative raw material purchase prices and higher quality standards.

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.Significance:We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.See related commentary by Fisher and Oh, p. 342.This article is highlighted in the In This Issue feature, p. 327

Supplementary Methods, Supplementary Figures 1-19, Supplementary References

The digital literacy that has developed in recent decades has resulted in internet playing an important role in the communication of wineries. Business websites, initially used as an exhibitor of products, quickly became one of the most important tools to implement communication strategies used to successfully place the wine product in a competitive market. The purpose of this study is to analyse major Italian wineries websites through textual statistics and text mining methods to provide evidence on the storytelling device adopted by these companies to promote and brand themselves. The information contained in the websites of the selected businesses in Northern, Central and Southern Italy, has been analysed in three steps. The first consisted in investigating categories with which the contents were organized, and the second step involved examining the contents’ word clouds which are useful for a qualitative analysis on similarities and differences found in the three different areas. Finally, different strategies were formalized, by reconstructing the structure of concepts underlying the communication models of the wineries of the three areas examined. The results demonstrate considerably different approaches adopted by the areas. While the wineries in Central Italy focus on communication concerning the company, in the North and South, more attention is given to production methods and territory respectively. Thanks to the analysis of word clouds it was also possible to expose the construct which is the basis of narratives used by wineries, followed by the typical communication strategy of the different Italian areas.

L'articolo si concentra sullo sviluppo di alcune filiere socialmente sostenibili emer-se negli ultimi dieci anni come forma di risposta dal basso allo sfruttamento del lavoro migrante. Si tratta, in particolare, di modelli di produzione-scambio-consumo che si inseriscono nell'ambito delle più ampie pratiche di resistenza alle trasformazioni del sistema agroalimentare, che fanno delle condizioni di lavoro dei braccianti di origine straniera un elemento centrale della "qualità" dei prodotti e della sostenibilità delle supply chain. A partire da uno studio realizzato nell'ambito di un progetto Fami, adottando un approccio qualitativo, il contributo ne analizza il ruolo degli attori coinvolti, le strategie adottate, le opportunità e i limiti dal punto di vista della creazione di lavoro sostenibile e dell'emancipazione dei lavoratori dallo sfruttamento.

The improvement in life expectancy, economic conditions, and technological and medical progress have radically changed the demographic structure of many societies. Since many countries now have an ageing population, by adopting a life-course study perspective, this paper aims to explore the needs of older adults (over 60), and the currently adult population which will become older in the coming decades (50–60 years). In detail, the study investigates the lifestyles of the target populations by focusing on two main areas concerning health (healthy diet; attitudes towards physical activity) and socio-relational-housing and living conditions (social housing, senior co-housing in rural environments, etc.). A qualitative study was carried out based on 16 in-depth interviews developed over one month (February 2022). The conduct of the interviews was supported by the Italian Center for Sensory Analysis (CIAS). Emerging from the results, the concept of active ageing is perceived by mature and older adults in a positive and optimistic way. The sample considered want to re-engage in life, continuing to be active, useful, and maintaining their self-esteem, social life and independence. However, despite older people’s major concerns being preserve their physical abilities and social integration, this target group adopts behaviours focused more on current well-being rather than worrying too much about how this well-being will change as they age.

Purpose The purpose of this paper is to deepen the global sourcing (GS) phenomenon from the acquiring firms’ viewpoint by analyzing the Italian craft beer sector. This industry has been chosen since it represents a perfect context for the GS activities’ analysis. Notably, different features characterizing this business force Italian breweries to turn to suppliers, located outside their national borders, to purchase the necessary raw materials. Design/methodology/approach The paper adopts a multiple case study concerning four Italian agricultural breweries located in the Marche region. Findings Results identify the main motivations, drivers, risks, obstacles and costs related to the adoption of the GS activities, by corroborating a positive interconnection with the GS literature findings. Research limitations/implications The main limitation is related to the fact that the study is based on a survey carried out on a specific region and product category. Therefore, future research could analyze other Italian regions and/or different types of products. Practical implications The study identifies different gaps characterizing the Italian supply market. Managerially these gaps can be converted into critical opportunities for the future development of the entire Italian brewing sector. Moreover, the results detect several actions the investigated breweries will seek to develop in the near future, which could strongly support the growth of the Italian beer sector. Originality/value The study deepens a topic little explored by literature, especially with reference to the supply activities of the Italian agricultural breweries.

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.

Although craft breweries are still a niche sector within a market dominated by industrial mass producers, the innovative aspects of the craft beer revolution could trigger interesting transformations in several contexts in Italy. This phenomenon has benefited from Italian creativity, combined with the ability of reinventing a tradition, which relies on imagination and contamination between local and global customs. On this respect, several craft breweries have adopted a global sourcing strategy, while other typologies (e.g., the agribrewers) usually use self-produced raw materials. In this context, this chapter investigates the drivers that may influence the adoption of different procurement strategies in agribreweries and craft breweries, also evaluating the impact of the procurement strategy not only on the firm’s competitiveness, but also on the product promotion and territory development. After analyzing the evolution of the craft beer industry in Italy, this study adopted mixed-method research in the Marche Region, discussing the results with several experts and local stakeholders.

Social farming (SF) has emerged as a social innovation practice shaping heterogeneous approaches and results. This study discusses the complexity of SF policy and practices, and it is led by the main hypothesis that the relationship between agricultural and social dimensions might be very heterogeneous, not only in different national contexts but also within the same national and local level. SF policy and practices are investigated testing the hypothesis of three main different modalities of interaction according to how the social and the agricultural perspectives interact. In the first, social target is not involved in the production system of the farm and the farm is the context where actions and measures of a social nature take place. In the second type of interaction, the farm employs the beneficiaries in some of its production activities collaborating with the social services. The third is where the farm organizes its activities to actively employ targeted people to enhance their social inclusion and integration in the community. Italian SF policy and practices are analyzed as case study, through the lens of sociological critical discourse analysis regarding the regional regulatory documents, and interviews for local case studies. The results of the study show that SF policy and practices might be very heterogeneous also within the same national and local level, outlining different hybridization of social and agriculture actions that can be properly analyzed through the three SF model proposal. This study contributes to the broader debate on the various dimensions of sustainability, suggesting the need for further research on the efficiency of SF as local development model sustainable in economic, social and environmental terms.

This article aims to analyse the European pig sector and its transformations (e.g. vertical integration and phase specialization).In particular, we will both explore the specialization and territorial concentration of pig production, and the significant changes which have taken place in the trade among European Union countries. Using the network analysis (betweenness centrality, node strength and community detection) applied to Eurostat and fao datasets on production and trade in the period 2000-2016, we will show the emergence of national players and international connections that lead to a larger continental market. Finally, this evidence will be used in the discussion and conclusion to raise wider concerning the working of agrifoodvalue chains, in terms of social, economic and environmental sustainability, as well as regulation. This calls for more interdisciplinary analyses of value chains.

Purpose The purpose of this paper is to investigate the emergence of microbreweries in Italy over the last 20 years (period 1993-2014) and assess its main determinants. Design/methodology/approach The recent intense growth is expressed by the increasing number of entries in the sector actually accompanied, in most recent years, by an increasing number of exits. The paper proposes a quantitative assessment of this entry-exit dynamics through a sequence of econometric models known as survival models. Findings Together with two other orders of possible determinants (idiosyncratic characteristics and the exogenous evolution of the beer market), the paper assesses the role played by specific geographical and local factors within these dynamics. Estimation results show that, whereas market force and individual features unquestionably affect entry and exit choices, geographical and local factors are of limited relevance, especially for the recent entry dynamics. Originality/value Although the literature on the so-called craft beer revolution is already vast and increasing, the novel contribution of the paper concerns the specificity (if any) of the Italian case and the role of spatial factors in this respect. This investigation is performed adopting an advanced quantitative approach and this attempt is also quite original within this literature.

Introduction: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor family that regulates gene expression programs contributing to inflammation and cell survival. NF-κB signaling occurs via two branches: classical and alternative, and is often enriched in somatic mutations of key pathway members in several lymphoid malignancies. Here, we reveal deregulation and constitutive activation of the alternative NF-κB pathway in a subset of DLBCL patients with recurrent genomic loss of the gene encoding tumor necrosis factor receptor-associated factor 3 (TRAF3), a regulator of the NF-κB signaling pathway. Methods and Results: To uncover novel driver mutations of DLBCL pathogenesis and tumor maintenance, we performed Affymetrix SNP6.0 copy number analysis on 347 de novo DLBCL samples from patients uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). We observed frequent, focal genomic loss of chr:14q32.31-32 which included TRAF3 and RCOR1 (7%, 22/313) in the minimally deleted region and an enrichment of activated B-cell-like (ABC) subtype cases over germinal center B-cell-like (GCB) subtype cases, confirming previously published data (Chan et al, Blood 2014). RNAseq of these DLBCL samples revealed a significant reduction of TRAF3 mRNA in chr:14q32.31-32 deleted cases compared to copy number neutral cases (p=0.002). Next, we focused on characterizing the phenotypic consequences of TRAF3 loss in DLBCL. We used CRISPR/Cas9 gene editing to knock out TRAF3 in 2 GCB-DLBCL (DOHH2, OCI-LY1) and 2 ABC-DLBCL (HBL1, OCI-LY3) cell lines. We performed immunoblotting analysis of NF-κB pathway members on cell fractionated samples of TRAF3 knockout cells and found increased levels of the NF-κB inducing kinase NIK (a direct target of TRAF3-mediated ubiquitin-proteasome degradation) and a concomitant increased nuclear translocation of NF-κB transcription factor complex subunits RelB and p52. Proteasome blockade restored RelB cytoplasmic localization and reduced processed p52 protein in TRAF3 knockout GCB-DLBCL lines only, indicating other factors may contribute to alternative NF-κB activation in ABC-DLBCL. Moreover, classical NF-κB activation remained unaffected, highlighting the specific role of TRAF3 regulation on the alternative NF-κB pathway in DLBCL. Consistent with these findings, TRAF3 knockout cells exhibited NF-κB-dependent transcriptional upregulation by luciferase reporter activity and elevated pro-inflammatory cytokine production (IL-6, TNF-β) by Luminex and ELISA. To study transcriptome changes as a result of TRAF3 loss-of-function, we performed RNAseq and differential gene expression analysis on wildtype and TRAF3 knockout DLBCL cell lines as well as primary DLBCL samples (N=347). We found enrichment of NIK and NF-κB associated pathways in TRAF3 deficient DLBCL and uncovered additional enriched gene sets including those involved in cell cycle regulation, cell division and metabolism, suggesting a potential proliferative and survival advantage. Conclusion: Our findings link TRAF3 loss-of-function to clinical and gene expression phenotypes in DLBCL and highlight alternative NF-κB activation as a pathogenically important pathway in both GCB and ABC subtypes. Future studies will be directed towards comprehensive evaluation of NF-κB inhibitors for effective blockade of constitutive alternative NF-κB activation in DLBCL. Disclosures Scott: NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding. Steidl:Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; AbbVie: Consultancy.

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and ‘eat-me’ signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation—a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited. Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. Significance: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints. See related commentary by Fisher and Oh, p. 342. This article is highlighted in the In This Issue feature, p. 327

The school canteen is a very effective tool to enhance the choices made by the government in terms of sustainability. The correct practices that should be adopted in the organization of canteens, starting from the procurement function of food, may have, in fact, a major impact in terms of support to local economies, environmental protection (preservation of natural resources and biodiversity, control of waste production and emission of greenhouse gases) and rural development. Furthermore, if the management of the canteen is paralleled by nutrition education activities aimed at promoting responsible consumption, user behaviour may change considerably, contributing to spread correct eating patterns, which are essential to counteract the phenomena of obesity and overweight, and for nimposing a culture of social and environmental responsibility.The realization of a school canteen that present requirements of economic, social and environmental sustainability is, however, a very complex task for the government, because of the multiple constraints introduced by the economic-financial legislation and socio-cultural environment, often hostile to the introduction of innovations.In this context, the aim of this work is to provide a contribution to the dissemination of sustainability practices in public procurement and, in particular, in school canteens. After having defined the theoretical framework, considering the realization of a sustainable canteen project as a wicked problem, whose orientation can be facilitated through the implementation of a business model, some possible practices related to the design of a more sustainable school canteen are individuated. Subsequently, the elements of a Business Model Canvas are illustrated, considered an effective tool for public authorities (even of modest size municipalities), interested to implement a school canteen service that is able to combine local development with environmental protection and the health of children.

Background: With the goal of translating biological discovery into clinical actionability, deciphering crosstalk in the cellular ecosystem of the tumor microenvironment (TME) has emerged as a research focus. Although comparatively little is known about the immune biology of diffuse large B-cell lymphoma (DLBCL), as reflected in clonal selection of specific somatic gene mutations in response to immune system pressure and the specific composition of the TME, PRAME has emerged as a prominent member of the cancer germline antigen/ tumor associated antigen (TAA) family of proteins. It is expressed in various types of cancers, but generally not in normal tissues, apart from male germinal cells, and triggers autologous T-cell mediated immune responses. PRAME is highlighted as a new cancer therapeutic target of T-cell or antibody-based immunotherapies with promising anti-tumor responses in early phase clinical trials and pre-clinical models for several types of cancers. In the context of developing new immunotherapies, targeting TAAs that are presented by major histocompatibility complexes on tumor cells is a promising therapeutic strategy for patients that experience treatment failure. Material and methods: We performed integrative genomic analysis of whole-transcriptome RNAseq, targeted genomic sequencing, and high-resolution copy number analysis in 347 de novo DLBCL tumors from patients uniformly treated with R-CHOP. Findings were correlated with pathological and clinical parameters, as well as TME composition. Using DLBCL-derived cell lines (7 EZH2 mutated and 5 wt) and CRISPR-Cas9 genome editing, we performed in vitro functional studies to characterize cell-intrinsic effects of PRAME knockout. Moreover, we studied EZH2 inhibition in a murine model of Ezh2 mutant lymphoma with a focus on mechanistic links between EZH2 activity and PRAME expression, as well as TME composition (cell-extrinsic effects). Results: We discovered recurrent, and highly focal deletions of 22q11.22 including the PRAME gene, which were associated with poor treatment outcome, independent of pathological and clinical risk factors. To explore PRAME-deletion-associated phenotypes and interaction with the tumor microenvironment (TME), we analyzed corresponding RNAseq, immunohistochemistry (IHC), and flow-cytometry data from our DLBCL cohort and utilized enzyme-linked immunospot (ELISPOT) assays using patient-derived peripheral blood mononuclear cells. PRAME deletions contributed to an immunologically "cold" TME, representing a somatically acquired mechanism to evade anti-tumor T-cell response (cell-extrinsic effect). Using PRAME knock out by CRISPR-Cas9 in vitro, TRAIL-mediated apoptotic signaling was impaired. In addition, PRAME down-modulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. Using proximity ligation assays and co-IP, we demonstrated that PRAME directly interacted with EZH2 as a negative regulator, establishing a link between PRAME deletions and EZH2 mutations with anti-apoptotic signaling in DLBCL (cell-intrinsic effect). An in vivo murine model of Ezh2 mutant lymphoma showed decreased T-cell infiltration in the TME and Ezh2 inhibition induced PRAME restoration as compared to vehicle controls. IHC for CD3, CD4, FOXP3, and GZMB revealed significant increases in various T-cell populations of the TME, including Tregs and cytotoxic T cells. EZH2 inhibition with EPZ-6438 abrogated these dualistic effects leading to increased immune cell infiltration in the tumor microenvironment and acceleration of apoptosis via PRAME restoration. Moreover, restoration of PRAME antigen presentation by EZH2 inhibition resulted in enhancement of PRAME binding using a T-cell receptor mimic PRAME antibody (Pr20), suggesting immunotherapeutic potential. Conclusion: Our findings highlight multiple functions of PRAME during lymphomagenesis. PRAME restoration by EZH2 inhibition provides a preclinical rationale for synergistic therapies combining epigenetic re-programming with PRAME-targeted therapies. Disclosures Dao: Eureka Therapeutics: Consultancy. Melnick:Jubilant: Consultancy; Epizyme: Consultancy; Constellation: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Research Funding. Scheinberg:Lantheus: Current equity holder in private company; Eureka Therapeutics: Consultancy, Current equity holder in private company, Patents & Royalties: Eureka Therapuetics and MSKCC have filed patent on this ScFV and TCRm; Actinium: Consultancy, Current equity holder in private company; Contrafect: Current equity holder in private company; Sapience: Consultancy, Current equity holder in private company; Iovance: Current equity holder in private company; Enscyse: Current equity holder in private company; Arvenas: Current equity holder in private company; Pfizer: Consultancy, Current equity holder in private company; Sellas: Consultancy, Current equity holder in private company; Oncopep: Consultancy. Scott:Janssen: Consultancy, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Celgene: Consultancy; Roche/Genentech: Research Funding. Steidl:Curis Inc: Consultancy; Roche: Consultancy; AbbVie: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy.

Food waste is a relevant global problem due to its consequences on food security, economy, and environmental sustainability. This study focuses, in detail, on finding the main motivation for food waste among the young and the principal actions to prevent it. The paper focuses on Italian reality, since Western countries are partly accountable for wasting large amounts of food. What is more, the focus has been shifted specifically on to the youths and young adults, as they are the portion of the population that are most inclined to waste food. Data were collected using a questionnaire survey performed on a sample of n = 904 Italian consumers. In line with previous research, the results of this study confirm that avoidable food waste comes from three main behavioural antecedents: over preparation, excessive purchase, and inappropriate conservation. The research shows that food waste cannot be reduced by just one-way from the consumers, rather, it goes both ways, between consumers and retailers. Therefore, only holding the consumers accountable and expecting them to solve it will not solve the problem of food waste, marketing and retailers should also consider ethics when it comes to food distribution.

The so-called Italian craft beer revolution is a new phenomenon characterised by a rapidly growing number of microbreweries and popularity of their products. The evolution of the Italian craft beer sector has interesting potentialities in terms of local/rural development. The analysis is based on available statistics as well as on a survey carried out in May 2014 which discloses features, motivations and expectations of the craft beer producers. Together with the risk of overproduction due to the high number of recent entries, the creation of local supply chains (from barley cultivation to its transformation into malt) is emerging as a possible evolution of the sector, thanks to the advent of a new typology of microbrewery, the agricultural brewery.

This paper investigates the governance system of 12 Italian Organic Districts (ODs) with the purpose of evaluating the extent to which it adheres to Ostrom’s model (1990) concerning Common Pool Resources (CPRs) management. Starting from the definition of territory as a CPR, ODs can be defined as selforganized and governed communities, able to manage it in the three dimensions (environmental, social, and economic) of sustainability. Results show a partial adaptation of the OD model to Ostrom’s design principles. An exact match is not possible, as some of the features required to comply with these principles are not within the competence of the ODs. In fact, there is still a lack of an adequate control/monitoring and sanction system that limits their capability of governing the commons, i.e. the territory in this case. However, the participatory approach, that is inherent to the governance system of ODs, allows for a certain degree of adherence to Ostrom’s model of CPRs management. Two levels of adherence of the ODs to this model have been identified. The first one is implied in their nature and finds its legitimacy in the framework of rules and laws that regulates organic farming; the second level of adherence is a consequence of the ODs socio-institutional maturity.

The concept of the ‘postmodern consumer’ plays a central role in the debate, started in the early 80s, about economic, social and cultural changes in developed countries in the years following the end of the second world war. These changes were interpreted as a passage from modern to postmodern society. According to this literature, postmodern conditions have had a significant impact on the consumer, especially with regard to his/her psychological characteristics. In this new framework the consumer is viewed as someone more interested in the symbolic or cultural value of products and services than in their functional and utility value. At the same time, he/she is represented as an active player in the market scenario, exercising the freedom to move in search of trademarks, symbols and experiences through which he/she can communicate his/her own identity. The figure of the postmodern consumer is difficult to place in the framework of standard neoclassical theories on consumerism, which highlights the shortcomings of this theoretical approach in studying the behavior of the postmodern consumer. These shortcomings are likely to be more relevant when considering the consumer of food products, given the strong nexus between consumption and the well-being of the consumer and the symbolic and cultural value that food products project. The main goal of the paper is to provide an interdisciplinary overview of the postmodern consumer of food products by means of an analysis of scientific literature, mainly in the areas of behavioral economics, sociology and psychology. Following this, the paper focuses on questions regarding information and the rational behavior of consumers as being the main hypothesis upon which standard neoclassical theories are based, adding to the traditional approach to consumer choice the new insights provided by this different perspective. Finally, the implications of this type of analysis for food safety and quality policies are considered, together with a discussion on further research needed to define more effective policies.

Today the Mediterranean region faces major food security challenges in a delicate transition period following the 2008 economic crisis and the wave of social and political transformations that started in late 2010 and early 2011. Food security in the region is a challenge for many reasons. The demand for food is expected to increase by the mid-century because of population growth and shift in dietary patterns. Structural changes in the demand for food will require a substantial increase in food supply in a scenario progressively weakened by the lack of two strategic resources for agricultural production - fertile land and water -, the impact of climate, and greater instabilities in the global food market. These pressures raise the question of whether the principles and objectives that shaped the Mediterranean food system in the 20th century need revision in order to provide simultaneously enough food, in quantity and quality, to meet the nutritional needs of a growing population and to conserve natural resources for future generation. This volume aims at fostering dialogue and debate between decision-makers, stakeholders and scientific community of both shores of the Mediterranean, on the current challenges of the agri-food system and on the opportunities offered by a paradigm shift towards green/blue and circular economy.

Traditional Food Products (TFPs) represent an important standing point in enhancing the value of food production, and promoting economic and social development in many countries. The purpose of this chapter is to provide some insights about marketing strategies of small and medium-sized enterprises operating in the sector of TFPs, and to explore some of the most important features characterizing their competitive environment. In particular, the chapter will try to focus the attention on the main aspects concerning the legal protection of TFP within both the framework of World Trade Organization Agreement on “Trade Related Aspects of Intellectual Property Rights” and the European Union’s, as well as on the growing attention of current consumers toward the quality of food product, but also toward cultural, ethical, social and environmental issues involving production and processing of food products.

Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somaticIL4Rmutations in 15 out of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8 leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain-of-function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantagein vivoThe pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establishIL4Rmutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.

Introduction: The recently developed DLBCL90 NanoString assay robustly distinguishes primary mediastinal large B-cell lymphoma (PMBCL) from diffuse large B-cell lymphoma (DLBCL), as well as cell-of-origin (COO) subtypes of DLBCL (ABC, GCB, unclassified) and cases with a Double-Hit (DHIT) signature (Ennishi D., JCO 2019). When this assay was applied to biopsies from 343 patients with de novo DLBCL uniformly treated with R-CHOP, nineteen of these cases had a molecular PMBCL signature (mPMBCL), despite the fact that they were diagnosed as DLBCL based on their morphology, immunophenotype and clinical features. Here, we aimed to comprehensively characterize the molecular and clinicopathologic features of these mPMBCL cases. Methods: Survival estimates were calculated using Kaplan-Meier analysis, using time to progression (TTP) and disease specific survival (DSS) as endpoints. We applied whole-exome sequencing, copy number analysis (SNP6.0) and RNAseq to identify somatic mutations, copy number aberrations and differentially expressed genes, respectively. FISH was applied to assess the presence of rearrangements affecting MYC, BCL2 and BCL6. We used data previously obtained within our centre from a PMBCL cohort (n=73) to compare mPMBCL with "bona fide" PMBCL (PMBCL) tumors (Mottok et al, Blood 2019). Results: Median age at diagnosis was significantly higher for mPMBCL compared to PMBCL (62 vs 37 years, p Comparison of the mutational landscape of mPMBCL to PMBCL demonstrated perturbations in the central hallmarks of PMBCL pathogenesis: JAK/STAT signaling, NF-ĸB pathway activation and immune evasion. Genomic aberrations affecting JAK-STAT signaling were shared between mPMBCL and PMBCL, with SNVs or indels affecting IL4R, STAT6 and SOCS1 found in 37%, 37%, and 89% of mPMBCL and 36%, 40% and 69% of PMBCL, respectively. Moreover, copy number analysis revealed JAK2 amplifications in 44% of mPMBCL (71% of PMBCL) and differential gene expression analysis showed increased levels of CD274 (PDL1), PDCD1LG2 (PDL2) and genes belonging to the JAK-STAT-signaling network in mPMBCL. In contrast, these genetic aberrations were rarely observed in a recent whole-exome sequencing study on 304 primary DLBCL tumors (Chapuy B., Nat.Med. 2018). Mutations were also observed in NF-ĸB pathways but the patterns of mutations were distinct between mPMBCL (BIRC3 and BTK) and PMBCL (NKBIE) suggesting convergent biology with alternative mechanisms of pathway dysregulation. Similarly, mPMBCL harbored different mutations (CD83) implicated in immune evasion compared with PMBCL (B2M). Finally, we compared the mutational landscape of mPMBCL with recently described genetically-defined subgroups of DLBCL. Interestingly, a large majority of mPMBCL harbored at least one of the mutations characteristic of "Cluster 4" (incl. CD83, HIST1H1E, SGK1), a subset of DLBCLs defined by Chapuy et al that predominantly includes GCB-DLBCLs. Conclusion: We have identified and characterized a subgroup of DLBCL that expresses the PMBCL gene expression signature. Similar to bona fide PMBCL, these tumors are characterized by genomic aberrations that affect JAK-STAT, NF-ĸB signaling and immune response. However, our data suggest that dysregulation of the latter two pathways is established through distinct evolutionary modes that are reflected in differential mutation patterns and anatomical and clinical presentations. Our findings provide potential novel therapeutic avenues for this subset of lymphoma. Disclosures Sarkozy: Takeda: Research Funding. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy.

Introduction: Grey zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL), is a rare and poorly defined entity. To decipher its mutational landscape and discover new therapeutic targets, we performed exome sequencing of 31 GZL cases. Methods: GZL cases from the LYSA group (N=139) and BC Cancer (N=30) were centrally reviewed and classified as previously published (Sarkozy et al, Am J Surg Pathol 2019). Whole-exome sequencing was performed on 31 cases with available fresh frozen tissue, using laser micro-dissection (LMD, MMI technology) to enrich for tumor cells and obtain matching normal DNA from microenvironment cells. DNA was extracted (Agencourt® DNAdvance kit) and genomic libraries were constructed with the Ovation ultra-low kit (Nugen®). Exome capture was performed using Agilent SureSelectXT V6+UTR followed by paired-end sequencing (NextSeq®). Somatic nucleotide variants (SNVs) and indels were identified using VarScan, Strelka and Mutect. Parameters affecting the sensitivity and specificity of variant calling were optimized using 7 "gold standard" cases for which DNA from peripheral blood cells was additionally available. Possible oncogenic drivers were identified based on rate of recurrence, MutSigCV and literature review. Results: Among the 31 GZL cases, the median age was 41 y (14-83) with a sex ratio of 15M:16F; 21 cases had mediastinal involvement, including 15 within the thymic area; EBER in-situ hybridization (ISH) was positive in 8 cases. Seven (23%) cases were classified as group-0 (cHL morphology with 100% CD20 expression), 22 (71%) with an intermediate morphology as group-1 (N=9, cHL-like morphology) or group-2 (N=13, LBCL-like morphology) and 2 (6%) as group-3 (LBCL with 100% of CD30 expression). The mean coverage was 96X (42-203) for tumor samples. One case was excluded due to failure in the LMD process. Among the 30 cases, 6628 variants across 4826 genes were found, including 2903 coding mutations (325 indels and 2808 SNVs, mean of 104/sample, range: 15-678), 721 affecting the 5' UTR and 2774 the 3' UTR. A total of 152 genes were identified as being potential oncogenic drivers, with a mean of 11 mutated genes per case (range 2-36). The most recurrently mutated genes were SOCS1 (33%), B2M (23%), GNA13 (20%), LRRN3 (17%), and ZNF217, NCOR1, ITPKB, IRF2BP2, CSF2RB, and CSMD3 (13% each). The epigenetic SWI/SNF and transcription regulation pathway (including NCOR1/2, ARID1A, KMT2D, KMT2A) was affected in 73% of the cases, JAK/STAT in 70% and NF-kB in 19%. As assessed by CNVkit and GISTIC, the most recurrent gains/amplifications identified were in 9p24.1 (JAK2, CD274, PDCD2LG2; 69%) and 2p16.1 (REL, BCL11A; 62%), and losses in 11q14.3 (ATM; 48%) and 12q24.33 (NCOR2; 48%). Based on mutational signature analysis, individual base substitutions were linked to mutagenic processes, with the highest contributions associated with aging (29%) and defective DNA mismatch repair (27%); moreover, mutations attributable to AID/APOBEC activity (5%), were found to be significantly enriched in EBV- vs. EBV+ cases (p = 0.013). EBV+ cases had fewer total variants (mean 98 vs 258, p=0.08) and potential oncogenic variants (mean 7 vs 15, p=0.03) compared to EBV- cases. EBV+ cases also lacked mutations in the NF-kB pathway and MHC-class I components (B2M and HLA-B: 0% vs 43% in EBV-, p=0.06) but had mutations in STAT3, DHX58, ACTB and ATP13A4 (6/7 cases) not present in the 23 EBV- cases. LRRN3 and GNA13 mutations were significantly associated with thymic area involvement (40% vs 0%, p=0.01). Furthermore, fluorescence-ISH indicated that 20% (1/5) of EBV+ cases had a rearrangement in the CIITA locus (16p13.13) vs 53% (9/17) in EBV- cases. Patients with an intermediate morphology had more oncogenic variants than those in group 0 and 3 (mean of 15 vs 6 variants/case, p=0.01 affecting 12 vs 5 genes, p=0.004). Finally, NCOR1 (N=4) and NCOR2 (N=2) mutations were exclusively found in cases with intermediate morphology (23% vs 0% for those with group 0 or 3 morphology). Conclusion: These data suggest that GZL is a highly heterogenous disease harboring somatic driver events shared with PMBCL and HL. We also discovered novel gene mutations pointing to the importance of previously unrecognized pathways in the pathogenesis of GZL. The distinct mutational pattern in EBV+ GZL suggests divergent evolutionary trajectories. Disclosures Sarkozy: Takeda: Research Funding. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; BMS: Honoraria; Amgen: Honoraria, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Seattle Genetics: Consultancy; Bayer: Consultancy.

Inflammasomes are large multiprotein platforms that mediate the processing of caspase-1, which in turn promotes the maturation and release of IL-1β and IL-18 in response to microbial and danger signals. While the canonical pathway of inflammasome activation has been known for some time, a novel mechanism of noncanonical inflammasome activation mediated by caspase-11 was more recently identified. This pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1β, IL-18, and IL-1α, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. In this review, we gather together studies on both the mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, and discuss the emerging importance of this pathway in regulating host defense against intracellular bacterial pathogens.

The economic analysis of typical agri-food products requires to be focused on the following issues: i) the specific features of the offering system; ii) the technical restrictions established by the EU regulations on Protected designation of origin (Pdo and Pgi) and, iii) the strategies aimed at product differentiation and for value creation for the consumer. Considering this latest aspect, it is important to notice that the specificity of the agricultural raw materials, the use of traditional production techniques of production coming from the tradition of the place and certification represent only a prerequisite for the differentiation of the product on the market against standard products. The problem is that the specificity of local product comes from attributes (tangible and intangible) of quality which are not directly accessible, nor verifiable, by the consumer when he/she makes purchasing choices. This situation persists despite the greater propensity of modern consumer to make investments in information and his/her greater attention and larger background towards the acknowledgement of different offers based on quality. This paper tends to develop an analysis on a theoretical and operative basis upon open strategies that can be implemented at the enterprise level, and that of agro-food chain and of territorial system in order to promote the quality of products to consumers. In particular, the work addresses the problems connected to the establishment of competitive advantages for Protected Designation of Origin (Pdo) and Protected Geographical Indication (Pgi), highlighting that in order to achieve those advantages, firms offering typical products need to differentiate their offering on both material and immaterial ground acting on intrinsic and extrinsic attributes of quality of products, on specific features (natural, historical, cultural, etc.) of territorial, on the efficiency of the offering organizational structure, and finally on the presence of social and institutional specific networks. All these aspects point out the necessity of defining appropriate value strategies based on marketing principles which allow to translate the typicality of products into additional value for the consumer in order to enable the producers to acquire a premium price.

Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma, with patient outcomes inferior to most other lymphoma subtypes. Recent progress in describing recurrent somatic gene mutations has led to a better understanding of MCL pathogenesis. However, the functional and clinical implications of many alterations remain to be elucidated. Here, to uncover the role of recurrent UBR5 gene mutations in lymphomagenesis, we studied a cohort of 248 MCL patients by targeted sequencing and performed genome editing of MCL-derived cell lines to investigate UBR5-mutation associated phenotypes in vitro. We identified deleterious UBR5 exon 58 hotspot mutations in 8% of MCL patients, all of which were mutually exclusive with CCND1 mutations. Proteomics analysis of Granta-519 and Jeko-1 cell lines with engineered UBR5 exon 58 indel mutations showed differential expression of genes involved in cell cycle and ubiquitination, and led to the discovery of decreased phosphorylation of CCND1 in the UBR5-mutated lines. Accordingly, in vitro studies of engineered genome-edited Granta-519, Jeko-1 and Mino cells revealed accumulation of cells in the S phase of the cell cycle, increased phosphorylation of retinoblastoma protein (Rb), and increased lymphoma cell proliferation. Our results demonstrate that UBR5 mutations, in addition to the hallmark t(11;14) translocation drive proliferation of MCL cells, potentially rendering mutation-carrying cells more sensitive to targeted therapies. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Roche: Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding. Steidl:Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Tioma: Research Funding.

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is an important and conserved pathway in lymphocytes which is activated by extracellular stimuli such as cytokines and growth factors. Aberrant activation of the JAK-STAT pathway is a hallmark of a variety of lymphomas which leads to increased proliferation/survival as well as immune evasion. Regarding the latter, it has been previously described that activation of the JAK-STAT signaling pathway can alter the secretome of lymphoma cells and the composition of the tumor microenvironment (TME). Specifically, our group reported PTPN1 loss-of-function as well as IL4R gain-of-function (p.I242N) mutations up-regulate the expression of the immune regulatory chemokine CCL17 through a STATs-dependent mechanism in primary mediastinal B cell lymphoma (PMBCL). Here, we assembled a cohort of 340 diffuse large B cell lymphoma (DLBCL) patients uniformly treated with R-CHOP to investigate JAK-STAT signaling mutations (targeted gene sequencing), copy number alteration (SNP arrays), gene expression (RNAseq) and TME composition (Cibersort, IHC). We confirmed the presence of mutations in SOCS1, STAT6 and 9p24 amplification with a frequency of 13.8%, 2.5%, 11.4%, respectively. Interestingly, we also identified the presence of somatic IL4R mutations in DLBCL, including the hotspot p.I242N mutation previously reported in PMBCL. Similarly to what was reported for other alterations in the JAK-STAT pathway, IL4R mutations were significantly enriched in GCB-DLBCL as compared to the ABC subtype, unclassified or double hit lymphomas with DLBCL morphology (p=0.045). Within the GCB group, patients carrying mutations in IL4R showed inferior disease-specific survival (p=0.029) and time to progression (p=0.023) after R-CHOP therapy. Mutational analysis revealed IL4R mutation being significantly concurrent together with mutations in ACTB, KLML6, MYC, STAT6, NLRC5, TNFAIP3 and mutually exclusive with EZH2 mutations (p In summary, our data suggest a common mechanism between PMBCL and DLBCL where aberrant JAK-STAT activation mediated by mutations in IL4R plays a significant role in altering chemokine expression profiles and TME changes. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding. Steidl:Roche: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Tioma: Research Funding; Juno Therapeutics: Consultancy.

Background: The current standard of care in diffuse large B-cell lymphoma (DLBCL) consists of chemotherapy and therapeutic monoclonal antibodies that have significantly improved patient outcomes over the past 15 years. However, a large proportion of patients suffer from refractory or relapsed disease. Therefore, the development of new therapeutic strategies for this subgroup of patients, who are threatened by a high chance of disease-related death, represents an important unmet clinical need. Methods: We enrolled into our study 347 de novo DLBCL patients uniformly treated with R-CHOP from the BC Cancer population-based cohort between September 2000 and January 2012. RNAseq and high-resolution copy number analysis were performed and correlated with clinical outcome data and tumor microenvironment composition. We also performed functional studies to investigate PRAME-mediated memory T-cell responses and gene expression changes. Results: We discovered novel, highly focal deletions of 22q11.22, including the PRAME gene in 13% (44/338) of the cases. The deletions cluster in a narrow chromosomal region that includes a very small number of genes (VpreB1, ZNF280A/B, PRAME, GGTLC2, miR-650). Of clinical importance, 22q11.22 deletions were found significantly more frequently in germinal centre B-cell-like (GCB) type DLBCL (17% (31/180) vs. activated B-cell-like (ABC) type: 8% (8/98), P < 0.01), and were also significantly associated with worse outcome, which was specifically observed in GCB-DLBCL (5-year disease specific survival, non-PRAME-deleted: 84.5% vs. PRAME-deleted: 67.2%, P = 0.026). Homozygous deletions were more strongly associated with poor outcome than heterozygous deletions. Interestingly, 90% of PRAME-deleted cases were Ig-lambda restricted (P < 0.001). PRAME is a prominent member of the cancer testis antigen (CTA) family of proteins that are expressed in various types of cancers, but not in normal tissues, including normal mature B-cells, apart from male germinal cells. Due to the cancer-specific expression of CTAs, these molecules are considered promising targets for cancer immunotherapy using cytotoxic T-cells and tumor vaccination approaches. To determine the association with tumor microenvironment composition, we analyzed CD4/CD8 flow cytometry data from DLBCL patient samples. The numbers of CD4 and CD8-positive T cells were significantly lower in PRAME-deleted cases compared to wild type (CD4: P < 0.001, CD8: P = 0.013). Notably, RNAseq analysis revealed that the HLA-A*0201 genotype was seen significantly more often in PRAME deleted cases (PRAME wt: 2.5% vs. PRAME deleted: 10.8%, P = 0.005). In order to functionally characterize its interaction with the immune microenvironment, we utilized enzyme-linked immunoSpot (ELISPOT) assays to investigate memory T-cell reactions of patient-derived T cells to PRAME antigens using patient-derived peripheral blood mononuclear cells (PBMC) and measured IFN-g production (7 control healthy donors, 4 PRAME-deleted and 4-wild type patients). While T cells from PRAME-replete patients had no reaction to PRAME antigens, PRAME-deleted patient-derived T-cells had significant reactions to 4 independent PRAME peptides. These data suggest that PRAME-deleted tumor cells can escape from cytotoxic T-cell attack to gain growth advantage. Next, we performed PRAME knock-out (KO) experiments using CRISPR/Cas9 genome editing to clarify the cell autonomous effects of PRAME deletions. Using 2 different cell lines (Karpas422 and SUDHL-4), we found TNFSF10 (TRAIL) expression was significantly down-regulated in homozygous PRAME-KO cell lines compared to wild type. The soluble form of TRAIL (sTRAIL) was also reduced, as measured with enzyme-linked immunosorbent assays. These results suggest that PRAME downregulated cells may contribute to cell survival via TRAIL and sTRAIL reduction. Conclusion: We identified recurrent PRAME deletions and characterized their clinical and functional role in DLBCL. Our findings contribute to the understanding of cell-autonomous and extrinsic roles of PRAME deletions in lymphomagenesis and may lead to the discovery of new therapeutic avenues to simultaneously treat the tumor and the host. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Celgene: Consultancy, Honoraria. Steidl:Tioma: Research Funding; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy; Nanostring: Patents & Royalties: patent holding.

In this paper we provide an overview of some recent dynamic models of commercial fisheries. Our starting points are the papers by Okuguchi (Keio Econ Stud 35:9–17, 1998) and Okuguchi and Szidarovszky (Seoul J Econ 11(3):321–330, 1998) and Szidarovszky and Okuguchi (Seoul J Econ 13:471–476, 2000) on oligopoly competition in international fisheries, which are based on the assumptions of homogeneous fish population, homogeneous space and continuous time. Following also insightful hints given in Okuguchi (Keio Econ Stud 21:37–44, 1984) and Erjaee and Okuguchi (Keio Econ Stud 41:61–71, 2006), we describe how some heterogeneities can be introduced in fishery models. The examples provided in this paper include bioeconomic models of fisheries with several species and with different time scales, ranging from continuous-time to discrete-time dynamic models and also addressing hybrid models, where some variables evolve in continuous time whereas other ones change in (event-driven) discrete time. Fishery models where the aquatic environment is subdivided into adjacent patches, characterized by different fishing policies including, as a particular case, Marine Protected Areas, are also described. Finally, we describe a fishery models with cooperators and defectors and punishment policies to encourage cooperation. All the models described in this overview include an evolutionary mechanism, based on imitative behavior, through which fishers are allowed to change their harvesting strategy over time. Some of these models have been motivated by projects or management experiences performed in the Adriatic Sea by Italian fishing authorities.