Deployment of Next Generation Intrusion Detection Systems against Internal Threats in a Medium-sized Enterprise

In this increasingly digital age, companies struggle to understand the origin of cyberattacks. Malicious actions can come from both the outside and the inside the business, so it is necessary to adopt tools that can reduce cyber risks by identifying the anomalies when the first symptoms appear. This thesis deals with the topic of internal attacks and explains how to use innovative Intrusion Detection Systems to protect the IT infrastructure of Medium-sized Enterprises. These types of technologies try to solve issues like poor visibility of network traffic, long response times to security breaches, and the use of inefficient access control mechanisms. In this research, multiple types of internal threats, the different categories of Intrusion Detection Systems and an in-depth analysis of the state-of-the-art IDSs developed during the last few years have been detailed. After that, there will be a brief explanation of the effectiveness of IDSs in both testing and production environments. All the reported phases took place within a company network, starting from the positioning of the IDS, moving on to its configuration and ending with the production environment. There is an analysis of the company expectations, together with an explanation of the different IDSs characteristics. This research shows data about potential attacks, mitigated and resolved threats, as well as network changes made thanks to the information gathered while using a cutting edge IDS. Moreover, the characteristics that a medium-sized company must have in order to be adequately protected by a new generation IDS have been generalized. In the same way, the functionalities that an IDS must possess in order to achieve the set objectives were reported. IDSs are incredibly adaptable to different environments, such as companies of different sectors and sizes, and can be tuned to achieve better results. At the end of this document are reported the potential future developments that should be addressed to improve IDS technologies further

Distinct blood and visceral adipose tissue regulatory T cell and innate lymphocyte profiles characterize obesity and colorectal cancer

Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this asso- ciation remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (T reg ) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, γδ T, and T reg cell populations in VAT and blood of healthy lean subjects revealed that CD56 hi NK and OX40 + T reg cells are more abundant in VAT with respect to blood. Conversely, CD56 dim NK and total T reg cells are most present in the circulation, while γδ T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated T reg cells, and a concomitant preferential enrichment of OX40- expressing T reg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the V γ 9V δ 2/ γδ T cell ratio at systemic level. The alterations in the relative proportions of T reg and NKT-like cells in VAT were found to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes

The Ambiguity in Immunology

In the present article, we discuss the various ambiguous aspects of the immune system that render this complex biological network so highly flexible and able to defend the host from different external invaders. This ambiguity stems mainly from the property of the immune system to be both protective and harmful. Immunity cannot be fully protective without producing a certain degree of damage (immunopathology) to the host. The balance between protection and tissue damage is, therefore, critical for the establishment of immune homeostasis and protection. In this review, we will consider as ambiguous, various immunological tactics including: (a) the opposing functions driving immune responses, immune-regulation, and contra-regulation, as well as (b) the phenomenon of chronic immune activation as a result of a continuous cross-presentation of apoptotic T cells by dendritic cells. All these plans participate principally to maintain a state of chronic low-level inflammation during persisting infections, and ultimately to favor the species survival

La "Cultura" per il sistema produttivo. Alla ricerca di nuovi equilibri per una regolazione pubblica a vantaggio delle future generazioni.

En el canviat context normatiu de donar resposta a una crisi sanitària amb aquesta aportació, hem optat per limitar l'observació al tema de la "Cultura", d'aquí el títol "Cultura" en el teixit productiu. L'objectiu és intentar descriure què està passant a la llum del PNR i des dels objectius marcats per la Unió Europea. ens hem concentrat en l'ensenyament de Marc Fumaroli, així com membre de l'Académie française des de 1995. Fortament crític, expressa paraules dures sobre la "Cultura", tal com la va introduir André Malraux a França, [ja que] era el contrari del que la societat de consum exigia tàcitament per preservar la raó i la felicitat." Aquesta és la Metafísica de la "Cultura. "No és ni més ni menys que la fe, i ens sembla al que creiem". Fe oposada per l'educació liberal. ens vam posar en un intent de respondre-ho. El Primer és el tema del tema de recerca: què entenem per Cultura i Patrimoni Cultural? Quina és actualment la seva definició normativa? Què engloba? Quins són els canvis que dicta el nou article 9 de la Constitució? La segona pregunta que cal intentar respondre: quins són els models de regulació estatal del patrimoni cultural?En el contexto normativo modificado de la respuesta a una crisis sanitaria, esta contribución ha optado por limitar su observación al tema de la "Cultura", de ahí el título "Cultura" en el tejido productivo. El objetivo es intentar describir lo que está ocurriendo a la luz del PNRR y de los objetivos fijados por la Unión Europea. Nos centramos en la enseñanza de Marc Fumaroli, miembro de la Academia francesa desde 1995. Fuertemente crítico, expresa duras palabras sobre la "Cultura". como André Malraux la introdujo en Francia, [porque] era lo contrario de lo que la sociedad de consumo exigía tácitamente para preservar la razón y la felicidad". Esta es la Metafísica de la "Cultura". No es ni más ni menos que una fe, y nos parecemos a lo que creemos". A la fe se opone la educación liberal.In the changed regulatory context of responding to a health crisis with this contribution, we have chosen to limit the observation to the topic of "Culture," hence the title "Culture" in the productive fabric. The goal is to try to describe what is happening in light of the NRP and from the goals set by the European Union. we dwelt on the teaching of Marc Fumaroli, as well as a member of the Académie française since 1995. Strongly critical, he expresses harsh words about "Culture" , as André Malraux introduced it in France, [since] it was the opposite of what consumer society tacitly demanded in order to preserve reason and happiness." This is the Metaphysics of "Culture." It is neither more nor less than faith, and we resemble what we believe." Faith opposed by liberal education

OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection

Regulatory T (T reg) cells are the major obstacle to cancer immunotherapy, and their depletion promptly induces conversion of peripheral precursors into T reg cells. We show that T reg cells can be functionally inactivated by OX40 triggering. In tumors, the vast majority of CD4+ T cells are Foxp3+ and OX40bright. However, intratumor injection of the agonist anti-OX40 monoclonal antibody (mAb) OX86, but not anti-CD25 mAb, induces tumor rejection in 80% of mice, an effect that is abrogated by CD8 depletion. Upon intratumor OX40 triggering, increased numbers of infiltrating dendritic cells (DCs) migrate to draining lymph nodes and generate a new wave of tumor-specific cytotoxic T lymphocytes, as detected by tetramer and CD44 staining of node CD8+ T lymphocytes. Tumor-bearing Rag1-knockout (KO) mice reconstituted with OX40-deficient T reg cells and wild-type (WT) effector T cells, or the reciprocal combination, showed that both T reg and effector T cells must be triggered via OX40 for the tumor to be rejected. Accordingly, WT but not OX40-KO mice receiving intratumor coinjection of OX86 and ovalbumin protein were able to revert tumor-induced tolerization of adoptively transferred OX40-competent OTII T lymphocytes. In conclusion, OX40-mediated inactivation of T reg cell function unleashes nearby DCs, allowing them to induce an adaptive immune response. In addition, the known OX40-dependent delivery of fitness signals to activated T cells is boosted by concurrent T reg cell inhibition. OX40 triggering thus has multiple effects that converge to mediate tumor rejection

Digoxin and platelet activation in patients with atrial fibrillation: In vivo and in vitro study

Background-Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation (AF). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results-Post hoc analysis of a prospective study of anticoagulated patients with AF. Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11‐dehydro‐thromboxane B2 (TxB2), a marker of platelet activation, and serum digoxin concentration (SDC) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6-2.4 ng/mL) with or without prestimulation with a sub‐threshold of collagen. Median 11‐dehydro‐TxB2 was 105.0 (interquartile range, 60.0-190.0) ng/mg creatinine, and median SDC was 0.65 (interquartile range, 0.40-1.00) ng/mL. Urinary 11‐dehydro‐TxB2 and SDC were correlated (rs=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11‐dehydro‐TxB2 compared with non-digoxin users (P=0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects. Digoxin (2.4 ng/mL) induced calcium mobilization, PAC‐1 (procaspase‐activating compound 1) and platelet aggregation in AF patients but not in healthy subjects. After pretreatment with a sub‐threshold of collagen, digoxin dose‐dependent induced calcium mobilization, arachidonic acid release, TxB2 biosynthesis, PAC‐1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions-We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium‐related phospholipase A2 phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin

A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2.

OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40-null Treg diminished their ability to suppress inflammation in a model of lymphopenia-driven colitis. OX40-mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody-mediated depletion and defective turnover following thymectomy. In vitro, OX40-deficient Treg were found to be intrinsically hyporesponsive to IL-2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8+ and CD4+ T cells. A differential compartmentalization was detected between Helioshigh and Helioslow Treg subsets (thymus-derived versus peripherally induced): while Helioslow Tregs were enriched in both sites, only Helioshigh Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers

Mast cells (MC) are c-Kit-expressing cells, best known for their primary involvement in allergic reactions, but recently reappraised as important players in either cancer promotion or inhibition. Here, we assessed the role of MCs in prostate tumor development. In prostate tumors from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated (PD) foci that coexist in the same tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipients mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9 -/- MCs was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistently with epithelial-to-mesenchymal transition. Such a dual source of MMP-9 was confirmed in human tumors, suggesting that MCs could be a good target for early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. Taken together, these data underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer. ©2011 AACR

Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting