Breast cancer (BC) was not initially considered an immunogenic tumor; however, recent data show that immune-related factors are associated with patient prognosis and the response to treatment. Several large adjuvant clinical trials have shown that tumor infiltrating lymphocytes (TIL) are significantly associated with a better prognosis and can also predict responsiveness to pre-operative chemotherapy, particularly in the triple negative (TN) & HER2+ BC subtypes (Carsten Denkert et al. 2010; Loi et al. 2013a). Recently, the presence of ectopic lymph node-like structures characterized by distinct T and B cell zones, called tertiary lymphoid structures (TLS), were identified adjacent to the tumor (Gu-Trantien et al. 2013) in 60% of BC (Buisseret et al. 2017b) and linked with a good prognosis (Gu-Trantien et al. 2013). The mechanisms involved in TLS formation and activities and their impact on tumor immunity is relatively unknown. TIL infiltration and TLS formation are likely regulated, in part, by transcription factors (TF) that control cytokine/chemokine production within the tumor microenvironment (TME) (Pimenta and Barnes, 2014). One such TF, the forkhead box protein 1 (FOXP1) is abnormally expressed in various human tumors and has a known role in regulating immune cell functions. Contradictory data on FOXP1 expression together with a lack of information on its immune regulation led us to explore its role in this tumor type. The first part of this thesis research focused on FOXP1-mediated regulation in BC. Gene/protein analysis was examined in the four BC molecular subtypes, revealing its enriched expression in estrogen receptor positive (ER+) tumors (Luminal A/B). Luminal BC is generally less infiltrated compared with frequently high TIL infiltration in ER negative (ER-) tumors (i.e. HER2+ and TN) [reviewed in (Solinas et al. 2017a) and (Loi et al. 2014)]. We found that high FOXP1 expression in a cohort of untreated primary BC was significantly associated with a lower TIL and fewer TLS compared to FOXP1 low (FOXP1lo) tumors. This observation led us to investigate the effect of FOXP1 on cytokines and chemokines potentially involved in TIL recruitment and/or TLS formation. BC cancer cell lines were used to silence [MCF7; FOXP1hi] or overexpress [MDA-MB-231; FOXP1lo] FOXP1 expression. FOXP1 repression upregulated a number of cytokines and chemokines involved in T and B cell migration and function, while FOXP1 overexpression repressed a majority of the same factors. Expression analysis of the major T and B cell cytokine and chemokine genes was performed for FOXP1lo and FOXP1hi primary BC. These data reveal that FOXP1hi BCs have significant decreases in CXCL9, CXCL10, CXCL11, CXCL13, CX3CL1, CCL20, IL2, IL21, granzyme B and IFNγ and high levels of the immunosuppressive cytokines, IL10 and TGFβ. We next performed a lymphocyte migration assay using primary tumor supernatants prepared from FOXP1lo and FOXP1hi BC finding significantly decreased migration of total CD45+ lymphocytes, B cells, helper (CD4+) and cytotoxic (CD8+) T cells using FOXP1hi compared to FOXP1lo SN. Overall, our data suggest that FOXP1 plays an important role in repressing anti-tumor immune responses by negatively regulating TIL migration directed by specific cytokines and chemokines.The second part of this thesis research focused on the role FOXP1 plays in BC TLS. FOXP1 expression in T and B cell TIL and TLS was evaluated using RT-qPCR, multicolor flow cytometry, immunofluorescence (IF) and immunohistochemistry (IHC) and fresh, fixed and frozen breast tissues. Based on the FOXP1 expression two types of TLS were identified in BC: 1) TLS containing a germinal center (GC-TLS) and 2) TLS lacking a GC (non-GC-TLS). Examination of proteins specifically associated with active humoral immune responses allowed us to identify GC-TLS but not non-GC-TLS as functional. Gene expression analysis of micro-dissected tissues revealed distinct immune profiles that characterize B cell follicles in tonsils and spleen as well as aggregates, non-GC-TLS and GC-TLS in BC. This analysis further demonstrates that ongoing cell-mediated immune responses are associated with GC-TLS. The findings from this thesis research add important information to our understanding of how immune responses are initiated and maintained in BC and provide further insight into the identification and organization of functional immune responses at the tumor site. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

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The importance of security on the web is growing every day. How domains handle and prioritize their level of security is varying. Tradeoffs between security and convenience have to be made to uphold a website's public image. This thesis uses a subset of domains from the Alexa Top 1M list. The list was used to create our datasets, collected through active scans with testssl.sh. This thesis has through the mentioned datasets compared domains in regards to several security aspects and analyzed how they handle security and convenience. We performed our scans over the course of two weeks to analyze each domain's level of security. As well as looking at top domains for several popular categories. Our analysis mainly focused on comparing the domains on their choice of Transport Layer Security (TLS) version, cipher suite, support for HSTS, and if they were exposed to any vulnerabilities. The subset of domains that we looked at saw about 50% implementation of TLS 1.3. We discovered that the most popular domains tend to choose availability as one of their highest priorities, leaving them exposed to vulnerabilities in earlier versions of the TLS protocol. Most domains that showed exposure to one vulnerability, in general, also were exposed to BEAST. This was also the most prominent vulnerability among all domains. We also showed that many of the negotiated cipher suites on the list of domains still utilize cipher block chaining, which is known to be weak. Our results show that different browsers, mobile operating systems, and the time of day had a negligible impact on the choice of TLS version. Most of the domains in the popular categories had not yet adopted TLS 1.3 and were overall more exposed to the tested vulnerabilities than those on the top million list. The support for HSTS was low in both the categories and on the Alexa top list. We conclude that upgrading to the latest recommended standard should always be a priority for server operators.

Many network operators need to be able to ensure that customers get the level of service they pay for. To avoid bandwidth and server performance bottlenecks, and easily troubleshoot network problems, the network providers need to be able to see what payload data is sent. Modern networks encrypt data when sending it between nodes that makes passive monitoring more complex. A prevalent encryption mechanism on an IP-based network is TLS that needs to be decrypted.                This article’s purpose is to check if it is possible to decrypt TLS traffic in a passive monitoring system with the server’s private key. This is done by implementing a decryptor in a passive monitoring system in the programming language Java. The implemented solution intercepts the traffic, takes out relevant data from the traffic, and derives the session key from that data. How this is done is dependent on what cipher suite is used for the session. Because of delimitations and lack of time the solution is only able to decrypt the cipher suite TLS_RSA_WITH_AES_128_CBC_SHA256. The result showed that it is possible to decrypt TLS traffic and should be possible for more than the specified cipher suite. But there exists a major problem that's called forward secrecy. This is used in the key exchange algorithm called Diffie–Hellman and makes it impossible to decrypt with only server private key. The conclusion is that it is possible but because of forward secrecy, it is not recommended. TLS 1.3 only uses cipher suites with the key exchange algorithm Diffie–Hellman and the forward secrecy functionality is important for security.

Certificate Transparency provides auditability to the widely used X.509 Public Key Infrastructure (PKIX) authentication in Transport Layer Security (TLS) protocol. Transparency logs issue signed promises of inclusions to be used together with certificates for authentication of TLS servers. Google Chrome enforces the use of Certificate Transparency for validation of Extended Validation (EV) certificates. This thesis proposes a methodology for asserting correct operation and presents a survey of active Logs. An experimental Monitor has been implemented as part of the thesis. Varying Log usage patterns and metadata about Log operation are presented, and Logs are categorized based on characteristics and usage. A case of mis-issuance by Symantec is presented to show the effectiveness of Certificate Transparency.

Computer Aided Design (CAD) applications have historically been based on a single user per application architecture. Although this architecture is still popular to date, it does have several drawbacks. First of all the single user CAD architecture inhibits a concurrent engineering design process where several designers can work on the same model simultaneously. This limitation introduces time inefficiency especially when a project involves geographically dispersed designers. A solution to these drawbacks could be a transition from the traditional single user CAD architecture to a multiuser collaborative architecture. Advances in computer networking technologies, especially relating to the Internet, have provided the needed tools to make this transition a reality, thus making it possible for designers to simultaneously work on geometric models from one or more networked computers regardless of the location of the user. This new paradigm is expected to improve collaboration and greatly reduce product design times and consequently reduce cost and improve productivity. The multi-user architecture will, however, also require reliable security mechanisms to ensure its successful deployment in an enterprise environment where protection of intellectual property is of critical importance. This thesis proposes a framework to implement authentication, authorization and secure data communications in a multiuser collaborative CAD software system. This framework has been tested on an emerging multiuser collaborative CAD system called v-CAx being developed at Brigham Young University.

Methods for Direction of Arrival, DOA estimation of multiple objects based on phased arrayantenna technology have many advantages in for example electronic warfare and radarapplications. However, perfect calibration of an antenna array can seldom be achieved. Thepurpose of this report is to study different methods for DOA estimation and how calibration-/modelerrors affect the results. Possible methods for quantifying these kinds of errors using measurement data are suggested. This thesis consists of essentially five parts. The different studies have been carried out using MATLAB simulations as well as theoretical considerations, i.e., calculations. In the first study, examples of the possible performance of four DOA algorithms, MUSIC, TLS-ESPRIT, WSF, and DML are provided. Results are given both with and without applying spatial smoothing. The latter scheme is used for handling correlated, or even coherent, sources. The results show that, for the considered scenarios, MUSIC performs the most consistently well, while the performance of DML is inferior. ESPRIT is well-performing when spatial smoothing is applied and performs the best when the angles of two signals are very close. It has been observed that WSF with weighting matrices for optimal asymptotic performance as well as spatial smoothing applied doesn’t perform well. When applying model errors to the systemin the second study, the corresponding conclusions about the algorithms can be drawn. That separation distance between the angles and that higher SNR results in better estimates are also confirmed. Quantification of certain array errors is also considered using methods inspired by a scheme proposed in the context of nonlinear system identification. The results show that the DOA algorithms are very good at dealing with noise and that the attempted method works well when the model error is like the true signals, but different enough that it is not confused with a problem with more signals. The model error that results in the worst results is when it only affects some ofthe channels in the antenna array. The fourth study explores DOA estimation using extended Kalman filtering and concludes that it is a very good tracker of the angle over time for the considered scenarios. All of this is then applied to measured data, but due to either extensive model error, errors with processing the data, or both, the results are worse than expected. Simulations that try to replicate the measured data results in good angle estimation for the DOA algorithms. The Kalman filter also performs well in simulations.

Today, security has become a growing concern for all internet users, where technology is developing faster than its security is implemented, which leads to insecure domains. In this thesis, we look at the reality of today’s domains and research if some categories of domains are safer than others and the reason behind it. The total amount of researched domains was 8080 divided into four categories; popular, categories, continents, and malicious. The analysis was made by looking closer at default protocols, cipher suites, certificate authorities (CAs), certificate classifications, page loading times, and vulnerabilities. Our result indicated that TLS 1.2 and TLS 1.3 are the most commonly used protocol. The largest difference between the domains could be seen among the CAs, even though no definite reason for this could be found. The most popular cipher suite for popular, categories, and malicious belonged to TLS 1.3 meanwhile, continents had a cipher suite belonging to TLS 1.2. All four categories were vulnerable to at least five out of eight different types of attacks. The least commonly used certificate classification is EV certificates, while DV is the most commonly used. Through our data collection and analysis, we could conclude that all domains are not as safe as one might think, while the underlying security infrastructure of malicious domains might be better than anyone expects.

Today’s rail industry is under great demand. People will use trains even more in the future. Rail industry has to develop and integrate new systems towards a secure transportation system. One of these steps is investigated in this master thesis. Until now, many sensitive and vital data were transferred by using old methods like USB storage devices. In this master thesis, a new and secure way to store authentication keys in a central database is described as well as a secure way of communication between this database and the RBC entities. Different technologies are used and have as result the proposed goal. The creation of a database with PHP and the implementation of a server-client communication using TLS and HTTPS are described in this project. Improvements and future development of the project are discussed at the end. / Det råder hög efterfrågan på dagens järnvägsindustri. I framtiden kommer ännu fler människor åka med tåg. Järnvägsindustrin måste utvecklas och skapa nya system för att uppnå säkra transportsystem. I denna avhandling kommer detta behandlas. Fram till idag har många känsliga och viktiga data överförts med gamla metoder såsom USB-stickor. I denna masteravhandling beskrivs ett säkert sätt att lagra autentiseringsnycklar i en central databas och även ett säkert sätt att kommunicera mellan denna databas och RBC-enheterna. Olika tekniker har använts med det uppsatta målet som resultat. Upprättandet av en PHP-databas och klient-serverkommunikation med TLS och HTTPS beskrivs i detta projekt. Förbättringar och framtida utveckling av projektet diskuteras i slutet.

The SSL/TLS protocols over HTTPs main tasks are to encrypt communication and provide verification to the user that the website is the one it is claiming to be. With an increase in egovernment and agencies using e-services where sensitive information can travel over the Internet the need for SSL/TLS has increased and will continue to increase. This study therefore aims to provide answers to how the Swedish agencies have configured their websites in terms of SSL/TLS and why they are at their current level of security in regards to SSL/TLS. A technical survey using the tool Qualys SSL Server Test was used in order to collect the configurations. Follow up interviews with a semi-structured qualitative approach was then used to answer the second research question of what factors affect why they had their current security level. 48,77% of agencies had some sort of implementation but the majority did not use SSL/TLS. The ten most common factors which affected agencies security levels was “Projects”, “Availability”, “Attitude towards security”, “Perceived sensitivity of data”, “Consultants”, “Resources”, “Knowledge of SSL”, “Security responsibility”, “Eservice”, and “Laws or other externa influence”.