Identification Of Vulnerabilities Research Articles

Synthetic Vulnerabilities in the KRAS Pathway.

Simple SummaryDespite recent dramatic progress, developing drugs that target oncogenic KRAS or its key effectors remains a major challenge for cancer research. Improving our understanding of the underlying biology of KRAS in cancer will identify potential codependent vulnerabilities or synthetic lethal partners that are essential specifically in the context of KRAS mutations. Aberrant alterations in the KRAS oncogene not only favor cancer cell survival and proliferation, but also trigger oncogenic stress and compensatory mechanisms in cancer cells. These effectors are, thus, rational targets for defining synthetic lethal approaches to form the basis for effective therapies directed at KRAS-mutant tumors.Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

RARE-24. The use of novelin vitro models to study adamantinomatous craniopharyngioma disease biology and drug response

BACKGROUND: Challenges around the design and investigation of cell culture models of adamantinomatous craniopharyngioma (ACP) have arisen from the cellular heterogeneity of these tumors, with populations that harbor disparate requirements in culture. Novel approaches to in vitro modeling of ACP are needed. METHODS: Intraoperatively collected tumor specimens were mechanically digested and plated under conditions tailored to the cell population of interest. ACP tumor-derived fibroblasts and epithelial cells were isolated using serum-containing and keratinocyte-specific media respectively. ACP-derived epithelial cells were immortalized via SV40 virus transfection and puromycin treatment for stable cell-line generation. Cell line validation included immunofluorescence with markers appropriate for the cell population of interest. RNA sequencing of cell lines was compared to ACP transcriptome reference data. Cell typing was conducted using short tandem repeat sequencing. RESULTS: ACP fibroblasts and ACP epithelial cells maintained spindle-like and cobblestone morphologies respectively, even after 4 passages. Immunofluorescence staining confirmed high levels of Vimentin expression in ACP-derived fibroblasts, and panCK and B-catenin in ACP-derived epithelial cells. Point mutation in exon 3 of the CTNNB1 gene was identified in ACP-derived epithelial cells. CONCLUSION: Initial limits related to cell line development in ACP may be addressed through the isolation and culture-specific ACP cell populations. This experience demonstrates the maintenance of validated markers of the cell populations of interest ex vivo. While preliminary, such cell lines offer promise as tools for the identification and study of potential therapeutic vulnerabilities in ACP.

Vulnerability Identification and Remediation of FDI Attacks in Islanded DC Microgrids Using Multiagent Reinforcement Learning

This article proposes a novel approach to uncover deficiencies of the existing cyber-attack detection schemes and thereby to serve as a foundation for establishing more reliable cybersecure solutions, with particular application in dc microgrids. For this purpose, a multiagent deep reinforcement learning (RL)-based algorithm is proposed to automatically discover the vulnerable spots in the conventional index-based cyberattack detection schemes and automatically generate coordinated stealthy destabilizing false data injection (FDI) attacks on cyber-protected islanded dc microgrids. To enable a continuous action space for the trained RL agents and enhance the algorithm’s precision and convergence rate, deep deterministic policy gradient is incorporated. Using this approach, susceptibility of a state-of-the-art detection scheme to several different coordinated FDI attacks on the distributed communication links is identified. The proposed algorithm is also enhanced with a sniffing feature to enable maintaining the stealthy attacks even under the sudden disconnection of any of the compromised links. To address the discovered deficiencies within the index-based detection scheme, a complementary multiagent RL detection algorithm using deep <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$Q$</tex-math></inline-formula> -network algorithm is integrated, which provides a more reliable overall identification performance. Taking into account the communication delays and load changes, the effectiveness of the proposed algorithm is verified by the experimental tests.

The pain conductor: brainstem modulation in acute and chronic pain.

It is well established in experimental settings that brainstem circuits powerfully modulate the multidimensional experience of pain. This review summarizes current understanding of the roles of brainstem nuclei in modulating the intensity of pain, and how these circuits might be recruited therapeutically for pain relief in chronic and palliative settings. The development of ultra-high field magnetic resonance imaging and more robust statistical analyses has led to a more integrated understanding of brainstem function during pain. It is clear that a number of brainstem nuclei and their overlapping pathways are recruited to either enhance or inhibit incoming nociceptive signals. This review reflects on early preclinical research, which identified in detail brainstem analgesic function, putting into context contemporary investigations in humans that have identified the role of specific brainstem circuits in modulating pain, their contribution to pain chronicity, and even the alleviation of palliative comorbidities. The brainstem is an integral component of the circuitry underpinning pain perception. Enhanced understanding of its circuitry in experimental studies in humans has, in recent years, increased the possibility for better optimized pain-relief strategies and the identification of vulnerabilities to postsurgical pain problems. When integrated into the clinical landscape, these experimental findings of brainstem modulation of pain signalling have the potential to contribute to the optimization of pain management and patient care from acute, to chronic, to palliative states.

Polyploid giant cancer cells are dependent on cholesterol for progeny formation through amitotic division

Polyploid Giant Cancer Cells (PGCC) are increasingly being recognized as drivers of cancer recurrence. Therapy stress promotes the formation of these cells, which upon stress cessation often successfully generate more aggressive progeny that repopulate the tumor. Therefore, identification of potential PGCC vulnerabilities is key to preventing therapy failure. We have previously demonstrated that PGCC progeny formation depends on the lysosomal enzyme acid ceramidase (ASAH1). In this study, we compared transcriptomes of parental cancer cells and PGCC in the absence or presence of the ASAH1 inhibitor LCL521. Results show that PGCC express less INSIG1, which downregulates cholesterol metabolism and that inhibition of ASAH1 increased HMGCR which is the rate limiting enzyme in cholesterol synthesis. Confocal microscopy revealed that ceramide and cholesterol do not colocalize. Treatment with LCL521 or simvastatin to inhibit ASAH1 or HMGCR, respectively, resulted in accumulation of ceramide at the cell surface of PGCC and prevented PGCC progeny formation. Our results suggest that similarly to inhibition of ASAH1, disruption of cholesterol signaling is a potential strategy to interfere with PGCC progeny formation.

Disaster Risk Management Of Landslides In Peninsular Malaysia

Landslide is one of the major disasters that occur in Malaysia. Despite various initiatives undertaken by the government to reduce their occurrences, landslide incidents continue to occur, resulting in loss of life and property. The development process coupled with climate change increases the risk of landslides. This manuscript briefly looks at the causal factors of landslides and identifies requirements for landslide risk management to identify options to strengthen landslide risk management in Peninsular Malaysia. Risk management encompassing identification of hazards, vulnerabilities and exposure of elements can prevent landslides from becoming a disaster. The study conducted, noted that the present approach in landslide disaster management has not fully incorporated the landslide disaster risk management approach. Key aspects such as legislation, institutions, zoning of disaster risk areas, risk transfer mechanisms and financial allocations require serious consideration. The determination of the legal basis to incorporate risk management measures, which will set out the needed mandates, jurisdiction and responsibility is one of the important steps. It will help ensure that decision making processes are risk-based, and strengthen the processes in preparing disaster risk maps, comprehensive databases using landslide inventory and register. It would also help in the preparation of early warning and emergency response systems as well as bolster community involvement, awareness, and public education. These will require a holistic approach in landslide disaster risk management. It will support the effort undertaken by government and stakeholders to incorporate the four priority areas of the Sendai Framework for Disaster Risk Reduction 2015-2030 which can effectively help reduce the risk of landslides.

A survey form for the characterization of the historical built environment prone to multi-risks

The historical built environment (HBE) is constantly prone to many risks causing sudden (e.g., earthquakes and terrorist attacks) or slow (e.g., climate change-related and environmental pollution) onset of emergency conditions. Morphological, physical, and constructive characteristics are critically linked to system vulnerability and users’ exposure. In particular, open spaces (OSs) in the HBE represent typical attractors for the community in urban areas for leisure and touristic purposes and critical scenarios in case of a disaster. In fact, besides daily and hourly temporalities in everyday use, OSs also play a pivotal role in the immediate disaster response phases, considering sudden-onset events. Understanding which scenarios characterize OSs is critical to evaluate them from a multi-risk perspective and to propose effective mitigation strategies in multiple critical situations. To this end, this work offers a survey form template of the OS within the HBE according to a holistic but quick-to-apply approach. Placed in the context of the Project of Relevant National Interest (PRIN) BE S2ECURe, the survey form assesses the relationships between frontier elements and those contained in the OSs, focusing on literature-based identification of vulnerability, exposure, and hazard factors affecting risk. These factors are organized into five sections as the basis for classification criteria of OSs: (1) morpho-typological, (2) geometrical-spatial, (3) constructive, (4) use, and (5) context. The application to eight case studies contributes to the validation of the survey, showing its ability to trace both the level of complexity and the main characteristics of the analyzed scenario. Furthermore, the survey form can be properly and quickly applied by non-specialized technicians, such as local authorities, thus representing the first step to support planners in data collection and risk assessment of historical OSs.

The Referral Pattern in a Central Hospital in Iran During the First COVID-19 Peak: The Role of Media and Health Planning

Background: A better understanding of the pattern of epidemic-related referrals to healthcare centers might allow the identification of vulnerabilities and the required changes that the healthcare management system should undergo. Objectives: This study aimed to investigate the COVID-19 referral pattern and the role of media and health management planning in changing the trends. Methods: Data extracted from the electronic medical database of Imam Khomeini Hospital Complex (IKHC), located in Tehran, Iran, from February 20 to June 4, 2020 were examined. Individuals were divided into two groups, COVID-19 positive and negative. We used Google Trends to evaluate Google Internet search queries and also available policy documents, programs, and official news related to COVID-19 in Iran during the mentioned period. Results: In this study, 8647 individuals aged 46.05 ± 16.5 years were referred to IKHC. Approximately 57% were male, and 70% were COVID-19 positive. The most clinical symptoms were dyspnea, fever, cough, and myalgia. Chronic kidney disease (CKD) and type 2 diabetes mellitus were the most common underlying health conditions. In the first two weeks, the percentage of negative cases was higher than positive cases and then the pattern was reversed, when people searched for information about COVID-19 in media. Conclusions: Proper and timely information and education to people through the media and health management measures can be effective in reducing unnecessary visits to health centers, preventing the exhaustion of medical staff, and controlling the disease during epidemics.

Reliability evaluation of community integrated energy systems based on fault incidence matrix

• An analytical reliability evaluation method for CIESs based on fault incidence matrix (FIM) is proposed. • The energy-bus-based unified reliability evaluation model of CIESs is presented to describe the energy flows of the system in a unified matrix form. • The case study is performed based on a practical CIES to demonstrate the advantages of the FIMs in reliability index calculation and vulnerability identification. Reliability evaluation is essential for the planning, operation, and analysis of community integrated energy systems (CIESs). However, it is still challenging to quantify the reliability of CIESs accurately and efficiently because of the diverse energy characteristics and energy conversion relationships. In this paper, a reliability evaluation method for CIESs based on fault incidence matrix (FIM) is proposed to analytically demonstrate the impact of equipment failures on system energy supply. The energy-bus-based unified reliability evaluation model of CIESs is presented to describe the energy flows of the system in a unified matrix form. Three types of FIMs are constructed to reveal the different consequences of device failures on energy supply. The reliability indices of a CIES can be directly calculated through simple algebraic and Boolean operations based on the FIMs, improving the calculation efficiency significantly. The FIMs make it easy to identify the vulnerability segments of the system, which is desirable in the practice of device maintenance or upgrade to improve the reliability of the CIES. Case studies are conducted on a typical CIES to verify the effectiveness and feasibility of the proposed method.

At the feet of storytellers: Equity in early relational health conversations.

Early Relational Health (ERH) focuses attention on family-baby relationships during the first 1000 days of life. Positive ERH enhances child health and development and family wellbeing. Universal, early identification of RH and vulnerability could add value to care. How to screen, when, where, and with whom is the question. Tools and models for screening are practitioner-centered. Bias can affect family engagement and outcomes. This may be problematic for African American families. Authors present findings of a discourse analysis and phenomenological study of experiences of African American families' and HealthySteps Specialists' (HSS) of color with screening ERH in Washington, D.C., USA (N = 13). Findings indicate relevance, acceptance and utility may be influenced by positionality, cultural context, issues of equity, and engagement in mutual reflection. A family-centered approach that opened space for non-dominant knowledge about ERH made positive differences in engagement and utility for families and practioners alike. Health and vulnerability were detected reliably using this approach. Outcomes include new theories about ERH-focused visits with African American families and infants, and a new model for centering ERH in pediatric practice, entitled Early Relational Health Conversations. ERH-C is a family reflection model, not necessarily dyadic. It may have value for other populations. Future directions in ERH-C research are suggested.

Vulnerability Assessment of Groundwater in Industrialized Tiruppur Area of South India using GIS-based DRASTIC model

Abstract Identification of groundwater vulnerability is important in the utilization and protection of groundwater resources. The present study assessed vulnerability of the Tiruppur taluk of Tamil Nadu state in south India where the groundwater is increasingly polluted from industrialization (textile) and over population. Mitigation of this threat demanded a careful water resource management and thorough groundwater susceptibility assessment with the help of vulnerability map in DRASTIC index model and weighted overlay analysis method in GIS from the evaluation of depth to water table, net recharge, aquifer media, soil media, topography, impact of the vadose zone, and hydraulic conductivity. The drastic index map of this study classified the area into very low, low, medium, high and very high vulnerability and demarcated the areas of Mangalam, Mudalipalaiyam, Veerapandi, Peruntoluvu, Kettanur and Avanashipalaiyam as high and very highly vulnerable. Sensitivity analysis showed very low index for depth to water table (68 %), net recharge (79 %) and impact of vadose zone (75 %), indicating their higher influence on vulnerability. This vulnerability map might serve as a starting point for improving the management and planning of groundwater in this area.

The Tumor Suppressor Kinase LKB1: Metabolic Nexus.

Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.

Aquifer vulnerability identification using DRASTIC-LU model modification by fuzzy analytic hierarchy process

Aquifer vulnerability identification using DRASTIC-LU model modification by fuzzy analytic hierarchy process

STRATEGIC INPUTS OF COMPETITIVE INTELLIGENCE AND COMPETITIVE ADVANTAGE AMONG COMMERCIAL BANKS, IN KENYA

Purpose: This study sought to determine the effect of strategic inputs of competitive intelligence on competitive advantage among commercial banks in Kenya. Specifically, the study sought to determine the effect of market place opportunities, competitor threats, competitive risks, identifying and hedging against key vulnerabilities and verifying core assumptions on competitive advantage among commercial banks in Kenya. &#x0D; Methodology: A descriptive and explanatory research design was used in this study and primary data was collected at the head office of each bank which are all found in Nairobi City. Primary data was collected using a semi-structured questionnaire. Data was analyzed using both descriptive and inferential statistics. Analysis was done with the assistance of SPSS computer packages. &#x0D; Results: The results of the regression analysis found the coefficient of determination is R2= 0.847; indicating that 84.7% variation in competitive advantage among commercial banks in Kenya is explained by the strategic inputs of competitive intelligence. The Analysis of the Variance (ANOVA) value of F calculated was 27.602; this shows that the overall regression model was significant. The study established that all the five variables: marketplace opportunities, competitor threats, competitive risks, key vulnerabilities and core assumptions; the strategic inputs of competitive intelligence have a significant effect on the competitive advantage among commercial banks in Kenya.&#x0D; Unique Contribution to Theory, Practice and Policy: The study recommends to the management of commercial banks to improve and strengthen competitive intelligence activities which would help banks to quickly identify market place opportunities before they become obvious. Competitor threats should be discovered early to enable strategies to ameliorate or neutralize them be developed. Top management team should use competitive intelligence develop insights which can be transformed into an array of pre-emptive and responsive actions that enable the bank to be avert possible risks in the business environment. Bank managers should increase the frequency and scope of competitive intelligence activities that would enable them obtain critical information for rapid identification and assessment of key vulnerabilities so that they can hedge the banks against attack by rivals. The banks need to be continuously monitoring and verifying the core assumptions on which current strategies are grounded.

Preparing critical infrastructure for the future: Lessons learnt from the Covid-19 pandemic

The objective of this paper is to provide a view on the problem of insufficient state protection of critical infrastructure throughout the Covid-19 crisis. The paper looks at this problem with regard to the definition of critical infrastructure, its content, and also the limitations of current approaches to critical infrastructure protection. The examples relating to the Covid-19 crisis show the practices adopted and suggest possible steps forward. The research methodology implemented in this research is based on a critical analysis of the existing literature. The themes described in this paper show there is an urgent need to change current critical infrastructure protection approaches to a resilience-based modus operandi. Specifically, this paper highlights the need to shift the understanding of critical infrastructure from an object-oriented approach towards essential services/functions and to highlight its complex, socio- technical nature. It also highlights the deficiencies of current, prevention-based approaches to critical infrastructure protection such as the insufficient focus on identification and management process of vulnerabilities, especially in relation to (inter)dependencies resulting from interconnections with other systems. The gravity of the situation caused by the Covid-19 pandemic, despite its negative connotations, can be used as an opportunity to examine the real condition of protection of critical infrastructure. The pandemic suggests that there is much left to be done and because of the unpredictability of the future, we need to start acting as soon as possible.

Mapping Heat-Health Vulnerability Based on Remote Sensing: A Case Study in Karachi

As a result of global climate change, the frequency and intensity of heat waves have increased significantly. According to the World Meteorological Organization (WMO), extreme temperatures in southwestern Pakistan have exceeded 54 °C in successive years. The identification and assessment of heat-health vulnerability (HHV) are important for controlling heat-related diseases and mortality. At present, heat waves have many definitions. To better describe the heat wave mortality risk, we redefine the heat wave by regarding the most frequent temperature (MFT) as the minimum temperature threshold for HHV for the first time. In addition, different indicators that serve as relevant evaluation factors of exposure, sensitivity and adaptability are selected to conduct a kilometre-level HHV assessment. The hesitant analytic hierarchy process (H-AHP) method is used to evaluate each index weight. Finally, we incorporate the weights into the data layers to establish the final HHV assessment model. The vulnerability in the study area is divided into five levels, high, middle-high, medium, middle-low and low, with proportions of 3.06%, 46.55%, 41.85%, 8.53% and 0%, respectively. Health facilities and urbanization were found to provide advantages for vulnerability reduction. Our study improved the resolution to describe the spatial heterogeneity of HHV, which provided a reference for more detailed model construction. It can help local government formulate more targeted control measures to reduce morbidity and mortality during heat waves.

Design and Implementation of a Quantitative NetworkHealth Monitoring and Recovery System.

A network health monitoring system focuses on the quantification of the network’s health by taking into account various security flaws, leaks, and vulnerabilities. A plethora of propriety tools and patents are available for network health quantification. However, there is a paucity of available research and literature in this field. Thus, in this study, we present an architectural design of a network health monitoring system. The design focuses on the quantification of the network health of each end-user as well as the entire network. The network health score for each end-user is quantified by identifying (1) illicit egress-ingress traffic, (2) anomalous fingerprints, and (3) system-network vulnerabilities based on the NVD-CVSS (National Vulnerability Database, Common Vulnerability Severity Score) standards. An overall network-health score is produced, along with a prevention and recovery mechanism that is triggered upon the detection of an anomaly. The proposed system is implemented in a local area network and has demonstrated to protect the network against various threats successfully. The study is concluded by comparing the proposed tool with the popular propriety tools available in the field. The results outline that the proposed system garners features of open-source tools and enriches them by introducing a state-of-the-art architecture coupled with multiple novel features like exhaustive identification of vulnerability and detection of network aberrations using timers.

TERT promoter C228T mutation in neural progenitors confers growth advantage following telomere shortening in vivo.

Heterozygous TERT (telomerase reverse transcriptase) promoter mutations (TPMs) facilitate TERT expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this mutation is one of the earliest events in gliomagenesis. However, no appropriate human models have been engineered to study the role of this mutation in the initiation of these tumors. We established GBM models by introducing the heterozygous TPM in human induced pluripotent stem cells (hiPSCs) using a two-step targeting approach in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, and EGFRvIII overexpression. The impact of the mutation was evaluated through the in vivo passage and in vitro experiment and analysis. Orthotopic injection of neuronal precursor cells (NPCs) derived from hiPSCs with the TPM into immunodeficient mice did not enhance tumorigenesis compared to TERT promoter wild type NPCs at initial in vivo passage presumably due to relatively long telomeres. However, the mutation recruited GA-Binding Protein and engendered low-level TERT expression resulting in enhanced tumorigenesis and maintenance of short telomeres upon secondary passage as observed in human GBM. These results provide the first insights regarding increased tumorigenesis upon introducing a TPM compared to isogenic controls without TPMs. Our novel GBM models presented the growth advantage of heterozygous TPMs for the first time in the context of GBM driver mutations relative to isogenic controls, thereby allowing for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening.

Simple SummaryWe determined the sensitivity of several conjunctival melanoma cell lines to kinase inhibitors as well as a few other inhibitors using an image-based high throughput drug screening assay with 542 compounds. All cell lines demonstrated sensitivity to cell cycle inhibition, especially with polo-like inhibitors. The response to MAPK pathway inhibition was better in the presence of BRAFV600E mutations, while the response to PI3k/mTOR inhibition was better in the presence of the NRASQ61L mutation. Our study uncovers a large panel of new vulnerabilities in conjunctival melanoma and establishes the background for the expansion of therapeutic options in the management of this tumor.Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.

Code Polymorphism Meets Code Encryption: Confidentiality and Side-channel Protection of Software Components

In this article, we consider that, in practice, attack scenarios involving side-channel analysis combine two successive phases: an analysis phase, targeting the extraction of information about the target and the identification of possible vulnerabilities, and an exploitation phase, applying attack techniques on candidate vulnerabilities. We advocate that protections need to cover these two phases to be effective against real-life attacks. We present PolEn , a toolchain and a processor architecture that combine countermeasures to provide an effective mitigation of side-channel attacks: As a countermeasure against the analysis phase, our approach considers the use of code encryption; as a countermeasure against the exploitation phase, our approach considers the use of code polymorphism, because it relies on runtime code generation, and its combination with code encryption is particularly challenging. Code encryption is supported by a processor extension such that machine instructions are only decrypted inside the CPU, which effectively prevents reverse engineering or any extraction of useful information from memory dumps. Code polymorphism is implemented by software means. It regularly changes the observable behaviour of the program, making it unpredictable for an attacker, hence reducing the possibility to exploit side-channel leakages. We present a prototype implementation, based on the RISC-V Spike simulator and a modified LLVM toolchain. In our experimental evaluation, we illustrate that PolEn effectively reduces side-channel leakages. For the protected functions evaluated, static memory use increases by a factor of 5 to 22, corresponding to the joint application of code encryption and code polymorphism. The overhead, in terms of execution time, ranges between a factor of 1.8 and 4.6.